WO2025169089A1

WO2025169089A1 - Ophthalmic compositions of tyrosine kinase inhibitors and their uses

Info

Publication number: WO2025169089A1
Application number: PCT/IB2025/051225
Authority: WO
Inventors: Ajay Jaysingh Khopade; Arindam Halder; Vivek Patel; Raghavendra MUNDARGI
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2024-02-05
Filing date: 2025-02-05
Publication date: 2025-08-14
Anticipated expiration: 2026-08-05

Abstract

The present invention relates to a topical pharmaceutical composition of tyrosine kinase inhibitors for the prevention or treatment of posterior eye disease. The topical pharmaceutical composition of the present invention is useful to deliver a high concentration of an active pharmaceutical ingredient such as tyrosine kinase inhibitor in the posterior segment of the eye for example at a concentration of up to 10000 times higher than the IC₅₀ value of the active pharmaceutical ingredient.

Description

OPHTHALMIC COMPOSITIONS OF TYROSINE KINASE INHIBITORS AND THEIR USES

FIELD OF THE INVENTION

The present invention relates to topical pharmaceutical compositions of tyrosine kinase inhibitors. The invention also relates to the use of said topical pharmaceutical compositions for preventing or treating ophthalmological disorders such as age-related macular degeneration (AMD), diabetic macular edema, and/or diabetic retinopathy. More preferably, the invention relates to topical pharmaceutical compositions comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof and a solubility enhancer and its use for treating ophthalmological disorders such as age-related macular degeneration (AMD), diabetic macular edema, and/or diabetic retinopathy.

BACKGROUND OF THE INVENTION

Age-related macular degeneration, diabetic macular edema, and diabetic retinopathy are the leading cause of blindness worldwide. The AMD is characterized by progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a specialized area in the center of the retina and is recognized as dry and wet AMD, while macular ischemia is a major cause of irreversible vision acuity loss and decreased contrast sensitivity in patients with diabetic retinopathy.

Use of tyrosine kinase inhibitors such as axitinib, lenvatinib, pazopanib, and sorafenib in the treatment of AMD and diabetic retinopathy is known in the art. Various literature disclosed topical use of tyrosine kinase inhibitors in the treatment of AMD and diabetic retinopathy. U.S. Patent Application Publication Nos. 2015/0164790, 2014/0235678, 2011/0142923, 2015/0141448, Seo et al. "Inhibition of Corneal Neovascularization in Rats by Systemic Administration of Sorafenib" Cornea (2012) 3 1 (8), 907, the entire disclosures of which are incorporated by reference herein. Use of tyrosine kinase inhibitors and their topical compositions are disclosed in many patent literature such as US9539259, US10010610, US9572800, US20230089914, WO2017120600, US20230263907, WO2023103835, US20150164790, US20240285652, US20220023213, US20240285528, US20230210770, US20230118774, US20240285518, US20200306182, US10722396, US11534396, US11439592, US20240042713, US11883525, WO2024215649, US11369591, US20220096717, US11801310, US11369600, US12115246, US9968603, US11666533 and US11491240, the entire disclosures of which are incorporated by reference herein.

Despite the progress described in the art, there is a need for improved compositions and treatment methods. The topical compositions for ophthalmological applications should be capable of being easily administered without causing eye irritation, thus increasing patient compliance. The composition should also deliver an active agent to the posterior part of the eye at an effective concentration.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a topical pharmaceutical composition.

It is another objective of the present invention to provide a topical pharmaceutical composition for the prevention or treatment of a posterior eye disease.

It is a further objective of the present invention to provide a topical pharmaceutical composition to deliver high concentration of an active pharmaceutical ingredient in the posterior segment of the eye.

It is a further objective of the present invention to provide a topical pharmaceutical composition to deliver high concentration of a tyrosine kinase inhibitor in the posterior segment of the eye.

It is a further objective of the present invention to provide a topical pharmaceutical composition to deliver an active pharmaceutical ingredient (e.g. a tyrosine kinase inhibitor) in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC₅₀ value of the active pharmaceutical ingredient.

It is a further objective of the present invention to provide a topical pharmaceutical composition to deliver an active pharmaceutical ingredient (e.g. a tyrosine kinase inhibitor) in the posterior segment of the eye at a concentration at least 50 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

It is another object of the present invention to provide a topical pharmaceutical composition to meet any one or all of the objectives.

According to any one of the objectives, the topical pharmaceutical composition for ophthalmic administration.

SUMMARY OF THE INVENTION

In first aspect, the present invention provides a topical pharmaceutical composition for the prevention or treatment of a posterior eye disease.

In another aspect, the present invention provides a topical pharmaceutical composition to deliver a high concentration of an active pharmaceutical ingredient in the posterior segment of the eye.

In another aspect, the present invention provides a topical pharmaceutical composition to deliver a high concentration of a tyrosine kinase inhibitor in the posterior segment of the eye.

In another aspect, the present invention provides a topical pharmaceutical composition to deliver a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

In another aspect, the present invention provides a topical pharmaceutical composition to deliver a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 50 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

In one aspect, the present invention provides a topical pharmaceutical composition comprising an active pharmaceutical ingredient, its isomer, or a salt thereof, and a solubility enhancer.

In one aspect, the present invention provides a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, and a solubility enhancer.

In one aspect, the present invention provides a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, and one or more solubility enhancer.

In another aspect, the present invention provides a topical pharmaceutical composition comprising:

tyrosine kinase inhibitor, its isomer, or a salt thereof;
one or more solubility enhancer; and
one or more precipitation inhibitor.

In another aspect, the present invention provides an ophthalmic solution composition comprising:

tyrosine kinase inhibitor, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v; and
one or more pharmaceutically acceptable excipient.

tyrosine kinase inhibitor, its isomer, or a salt thereof in an amount of about 0.01% to about 5% w/v;
about 0.05% to about 10% w/v of methane sulfonic acid;
about 1% to about 20% w/v of sulfobutyl ether β-cyclodextrin;
about 0.05% to about 10% w/v hydroxypropyl methyl cellulose;
one or more pharmaceutically acceptable excipient; and
water.

In one aspect, the present invention provides a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, and a solubility enhancer.

In one aspect, the present invention provides a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, and one or more solubility enhancer.

axitinib, its isomer, or a salt thereof;
one or more solubility enhancer; and
one or more precipitation inhibitor.

axitinib, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v; and
one or more pharmaceutically acceptable excipient.

axitinib, its isomer, or a salt thereof in an amount of about 0.01% to about 5% w/v;
about 0.05% to about 10% w/v of methane sulfonic acid;
about 1% to about 20% w/v of sulfobutyl ether β-cyclodextrin;
about 0.05% to about 10% w/v hydroxypropyl methyl cellulose;
one or more pharmaceutically acceptable excipient; and
water.

In another aspect, the invention provides use of compositions for use in treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity.

DESCRIPTION OF THE DRAWING

: Represents Change in Corrected Total Lesion Fluorescence (CTLF) Value Over Time.

DETAILED DESCRIPTION OF THE INVENTION

The invention may be more fully appreciated and aspects, embodiments, or objects other than those set forth above will become apparent when consideration is given to the following description, including the following glossary of terms and examples. The skilled artisan will appreciate that additional preferred embodiments may be selected by combining the preferred embodiments above, or by reference to the examples given herein.

The active pharmaceutical ingredient may be referred to as a "drug". In the context of the disclosure, the active pharmaceutical ingredient is an ophthalmic drug, i.e. a compound that exhibits a therapeutic effect when administered in a sufficient amount to a patient suffering from an ocular condition.

The active pharmaceutical ingredient is a "protein kinase inhibitor" (PKI) that specifically blocks the action of one or more protein kinases. PKIs include, but are not limited, to protein kinase inhibitors and tyrosine kinase inhibitors, such as axitinib, afatinib, bosutinib, crizotinib, cediranib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, lestaurtinib, motesanib, mubritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, semaxanib, sunitinib, tandunitib, tipifarnib, vandetanib, and vemurafenib; or their isomers or salts or hydrates or solvates thereof, or combination thereof. In a preferred embodiment, the active pharmaceutical ingredient is a tyrosine kinase inhibitor selected from the group consisting of axitinib, ponatinib, sunitinib, lenvatinib, pazopanib, nintedanib, cabozantinib, vandetanib, sorafenib and regorafenib, or their isomers or salts thereof. More preferably, the active pharmaceutical ingredient is axitinib, or its isomers or salts thereof.

The term "tyrosine kinase inhibitor (TKi)" as used herein refers to a therapeutically active compound that is capable of inhibiting the activity of one or more tyrosine kinase, such as, for example, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR), and Fms-like tyrosine kinase-3 (FLT3). Examples of tyrosine kinase inhibitors suitable for use with the invention include, but are not limited to, axitinib, ponatinib, sunitinib, lenvatinib, pazopanib, nintedanib, cabozantinib, vandetanib, sorafenib and regorafenib or any combination thereof, their pharmaceutically acceptable prodrugs, isomers, hydrates, or salts thereof. Preferably, the tyrosine kinase inhibitors are axitinib, sunitinib, lenvatinib, pazopanib, and more preferably axitinib.

The term "salt" as used herein means those salts of a compound of interest that are safe and effective for the administration to a mammal. For a review of pharmaceutically acceptable salts see Berge et al., J. Pharm. Sci. (1977) 66, 1 - 19, incorporated herein by reference. Suitable salts for the purpose of the present invention include, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, mesylate, tosylate, besylate, esylate, etc.

The compositions may comprise the active pharmaceutical ingredient in free base form or salt form, i.e. as its inorganic or organic salt selected from the group consisting of propionate, acetate, 2,5-dihydroxybenzoate, citrate, malonate, sulfate, bisulfate, benzoate, maleate, tosylate, fumarate, succinate, tartrate, lactate, glycolate, phosphate, pyrophosphate, benzene sulfonate, ascorbate, chloride, bromate, malate, propionate, oxalate, isobutyrate, sulfonate, mesylate, esylate and pyroglutamate, as well as their isomers. The salts are preferably selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, tosylate, besylate, or esylate. The salts of axitinib, or its isomers are selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, tosylate, besylate, or esylate. The salts of lenvatinib, or its isomers are selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, tosylate, besylate, or esylate. The salts of sunitinib, or its isomers are selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, malate, tosylate, besylate, or esylate. The salts of pazopanib, or its isomers are selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, tosylate, besylate, or esylate. The salts of ponatinib, or its isomers are selected from, but not limited to hydrochloride, phenyl sulfonate, mesylate, tosylate, besylate, or esylate. In a preferred embodiment, the drug is present in free base form.

As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. The present invention encompasses all structural and geometrical isomers including cis, trans, E, and Z isomers, independently at each occurrence. The invention includes enantiomers, diastereomers, or racemates of the compound. Any combinations of the above features are also contemplated.

According to any one of the embodiments described herein, the active pharmaceutical ingredient is present in an amount from about 0.01% to about 10% w/v. For example, about 0.01%, 0.03%, 0.05%, 0.1%, 0.2%, 0.3%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% w/v. In one embodiment, the active pharmaceutical ingredient is axitinib, present in an amount from about 0.001% to about 10% w/v. In one embodiment, the active pharmaceutical ingredient is axitinib, present in an amount from about 0.01% to about 2% w/v. In one embodiment, the active pharmaceutical ingredient is axitinib present in an amount of about 0.125% w/v, preferably about 0.2% or 0.3% w/v. In another embodiment, the active pharmaceutical ingredient is lenvatinib mesylate present in an amount of about 0.2% w/v. In another embodiment, the active pharmaceutical ingredient is sunitinib malate present in an amount of about 0.4% w/v. In another embodiment, the active pharmaceutical ingredient is pazopanib hydrochloride present in an amount of about 0.25% w/v.

The percentage(s) or % expressed herein are based on the final volume of the topical pharmaceutical composition. The term "about" as used herein refers to as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value. As used herein, the term “about” means ±approximately 10% of the indicated value.

The terms "comprising" and "comprises" as used herein to be construed as open ended and mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited.

The term “mixing” or “mixture” as used herein refers to the addition of different compounds in a solid, semisolid, solution, or suspension state, irrespective of the sequence of addition to form a “mixture”. Wherein “mixture” can be a solid mixture, a clear solution, a hazy solution, or a suspension.

The terms “undissolved particles” as used herein refer to any particle of active drug and/or any excipient which is visible or having a particle size of D₉₀ more than 1 micron, 0.5 micron, 0.2 micron, 0.1 micron or 0.001 micron.

The terms "treat", "treating", "treatment" or “prevention” as used herein refer to administering a composition to a subject to achieve a desired therapeutic and/or clinical outcome in the subject.

In one embodiment, the terms "treat", "treating", "treatment" or “prevention” refer to administering an ophthalmic composition of the invention to reduce, alleviate, prevent, treat, or slow the progression or development of a disease such as posterior eye disease including but not limited to age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membrane (CNVM), cystoid macula edema (CME), epiretinal membrane (ERM) and macular hole, myopia-associated choroidal neovascularization, vascular streaks, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes of the retinal pigment epithelium (RPE), hypertrophic changes of the retinal pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retinal vein occlusion, retinitis pigmentosa, Stargardt's disease, Myopic Choroidal Neovascularization (mCNV), and retinopathy of prematurity.

Preferred posterior eye diseases include age-related macular degeneration (AMD) like dry AMD, wet AMD or choroidal neovascularization (CNV), diabetic macular edema, macular edema following retinal vein occlusion, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity. Examples of age-related macular degeneration (AMD) include but are not limited to dry or nonexudative AMD, or wet or exudative or neovascular AMD.

The term "subject" as used herein, refers to a warm-blooded animal such as a mammal, guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, rabbits, and humans are examples of mammals within the scope of the meaning of the term, preferably a human or a human child, which is afflicted with, or has the potential to be affected with one or more disease and condition described herein.

The phrase ‘Cyclodextrins’ refers to cyclic oligosaccharides containing 6 (α-cyclodextrin), 7 (β-cyclodextrin), and 8 (γ-cyclodextrin) glucopyranose monomers linked via α-1,4-glycoside bonds. The term “SBEβCD” as used herein refers to sulfobutyl ether β-cyclodextrin. The term “SBEγCD” as used herein refers to sulfobutyl ether γ-cyclodextrin. The amount of cyclodextrin in the ophthalmic composition of the disclosure typically may be from about 0.001% w/v to 50% w/v. Preferably, from about 0.001% w/v to 40% w/v. More preferably, from about 0.001% w/v to 30% w/v.

The phrase 'preservative efficacy test' (PET) or ‘Antimicrobial Effectiveness Test’ (AET) refers to a test laid down by regulatory authorities to validate the preservative efficacy of pharmaceutical preparations containing a preservative. Typically, preservatives are added in sterile pharmaceutical preparations that are meant to be used multiple times and not for single use. Such preparations are generally ophthalmic preparations, subcutaneous or intramuscular injections stored in multiple-dose containers. In such preparations, an antimicrobial agent or preservative is included to inhibit the growth of the micro-organisms. The Pharmacopoeias of various countries provide procedures and criteria to check whether the preparations pass the preservative efficacy test. For instance, according to United States Pharmacopoeia, the requirements for antimicrobial effectiveness are met if:

Log reduction in bacterial count at day 7 is not less than 1.0 log reduction from the initial calculated count; the "log reduction in bacteria" at day 14 is not less than 3.0 log reduction from the initial count; and there is no increase in bacterial count at day 28 compared to the previous reading at day 14.
There is no increase in counts of yeasts and molds from the initially calculated counts at 7, 14, and 28 days.
According to European Pharmacopoeia, sterile preparations like ophthalmic solution comply with requirement (criteria B) if the "log reduction in bacteria" at 24 hours is not less than 1.0 log reduction; the "log reduction in bacteria" is not less than 3 log reduction when tested at day 7; the "log reduction in fungi" is not less than 1 log reduction when tested at day 14 and when tested at 28 days there is no increase in the number of viable micro-organisms (bacteria or fungi) compared to the previous reading.

According to any one of the embodiments described herein, the preservative system used in the composition has sufficient antimicrobial activity to allow the composition to satisfy USP General Chpater〈51〉 antimicrobial effectiveness testing requirements.

The composition according to the present invention comprises tyrosine kinase inhibitor as a sole therapeutically active ingredient. It is present in an amount ranging from about 0.001% to 10% w/v, such as 0.001%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.125%, 0.2%, 0.3% w/v. The concentration (% w/v or % weight by volume) of tyrosine kinase inhibitor (axitinib, sunitinib, lenvatinib, pazopanib) as expressed herein refers to the concentration of base form.

In one embodiment, the present invention provides a topical pharmaceutical composition of an active pharmaceutical ingredient for the prevention or treatment of a posterior eye disease.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver a high concentration of an active pharmaceutical ingredient in the posterior segment of the eye.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC₅₀ value of the active pharmaceutical ingredient.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 8000 times higher than the IC₅₀ value of the active pharmaceutical ingredient.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 6000 times higher than the IC₅₀ value of the active pharmaceutical ingredient.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 4000 times higher than the IC₅₀ value of the active pharmaceutical ingredient.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 3000 times higher than the IC₅₀ value of the active pharmaceutical ingredient.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver an active pharmaceutical ingredient in the posterior segment of the eye at a concentration of up to 2500 times higher than the IC₅₀ value of the active pharmaceutical ingredient.

In one embodiment, the present invention provides a topical pharmaceutical composition of tyrosine kinase inhibitor.

In another embodiment, the present invention provides a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, and one or more solubility enhancer.

In another embodiment, the topical pharmaceutical composition further comprises one or more precipitation inhibitor.

In one embodiment, the present invention provides a topical pharmaceutical composition comprising:

According to any one of the embodiments described herein, the composition further comprises:

one or more preservative;
one or more pH adjusting agent; and
optionally one or more penetration enhancer.

In one embodiment, the present invention provides a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, one or more solubility enhancer, one or more precipitation inhibitor, one or more preservative, and one or more pH adjusting agent.

In one embodiment, the present invention provides a topical pharmaceutical composition comprising a tyrosine kinase inhibitor, its isomer, or a salt thereof, one or more solubility enhancer, one or more precipitation inhibitor, one or more preservative, one or more pH adjusting agent and one or more penetration enhancer.

In another embodiment, the composition is for ophthalmic administration, wherein the composition is a suspension, an emulsion, a solution, or a gel.

a tyrosine kinase inhibitor, its isomer, or a salt thereof from about 0.01% to about 10%;
one or more solubility enhancer from about 0.001% to about 30% w/v; and
one or more pharmaceutically acceptable excipient.

a tyrosine kinase inhibitor, its isomer, or a salt thereof from about 0.01% to about 10%;
one or more solubility enhancer from about 0.001% to about 30% w/v;
one or more precipitation inhibitor from about 0.05% to about 30%; w/v and
one or more pharmaceutically acceptable excipient.

In another embodiment, the topical pharmaceutical composition is an ophthalmic solution.

In another embodiment, the present invention provides an ophthalmic solution composition comprising:

a tyrosine kinase inhibitor, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v; and
one or more pharmaceutically acceptable excipient.

a tyrosine kinase inhibitor, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v; and
one or more pharmaceutically acceptable excipient.

According to any one of the embodiments described herein, the composition further comprises water as a vehicle.

According to any one of the embodiments described herein, the composition does not comprise any non-aqueous vehicle.

a tyrosine kinase inhibitor, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v;
one or more pharmaceutically acceptable excipient; and
water.

According to any one of the embodiments described herein, the tyrosine kinase inhibitor is selected from the group consisting of axitinib, ponatinib, sunitinib, lenvatinib, pazopanib, nintedanib, cabozantinib, vandetanib, sorafenib and regorafenib, their isomers or salts thereof.

According to any one of the embodiments described herein, one or more solubility enhancer is an acid selected from the group consisting of organic acid, mineral acid, or a combination thereof.

According to any one of the embodiments described herein, the precipitation inhibitor is selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof.

In one particular embodiment, the present invention provides an ophthalmic solution composition comprising:

a tyrosine kinase inhibitor in an amount of about 0.01% to about 10% w/v selected from the group consisting of axitinib, sunitinib, lenvatinib, pazopanib, their isomers or salts thereof;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v selected from the group consisting of organic acid, mineral acid, or a combination thereof;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof; and
one or more pharmaceutically acceptable excipient.

a tyrosine kinase inhibitor in an amount of about 0.01% to about 10% w/v selected from the group consisting of axitinib, sunitinib, lenvatinib, pazopanib, their isomers or salts thereof;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v selected from the group consisting of organic acid, mineral acid, or a combination thereof;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof; and
one or more pharmaceutically acceptable excipient; and
water.

According to any one of the embodiments described herein, the organic acid is selected from the group consisting of alkyl sulfonic acid, acetic acid, citric acid, malic acid, formic acid, lactic acid, oxalic acid, tartaric acid, uric acid, maleic acid, or a combination thereof.

According to any one of the embodiments described herein, the organic acid is alkyl sulfonic acid.

According to any one of the embodiments described herein, the alkyl sulfonic acid is selected from the group consisting of methane sulfonic acid, butane sulfonic acid, propane sulfonic acid, or a combination thereof.

According to any one of the embodiments described herein, the alkyl sulfonic acid is methane sulfonic acid.

According to any one of the embodiments described herein, the mineral acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, or a combination thereof.

According to any one of the embodiments described herein, cyclic polymer is selected from the group consisting of cyclic oligosaccharide, cyclic polysaccharide, cyclic non-oligosaccharides, or a combination thereof.

According to any one of the embodiments described herein, cyclic oligosaccharide is cyclosophoran, cycloamylose, cyclotetraglucose, cyclodextrin derivative selected from the group consisting of 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD), 2-hydroxypropyl-γ-cyclodextrin, methyl-β-cyclodextrin, carboxymethyl β-cyclodextrin, or a combination thereof.

According to any one of the embodiments described herein, the composition is free of γ-cyclodextrin. According to any one of the embodiments described herein, the composition is free of 2-hydroxypropyl-γ-cyclodextrin.

According to any one of the embodiments described herein, cyclic polysaccharide is cyclic β-1,2-glucan.

According to any one of the embodiments described herein, cyclic non-oligosaccharide is selected from the group consisting of cyclo poly(styrene), cyclo-poly(lactide), cyclo poly(ε-caprolactone) (PCL), cyclo poly(ethylene oxide) (PEO), or a combination thereof.

According to any one of the embodiments described herein, the linear polymer is selected from the group consisting of linear oligosaccharide, linear polysaccharide, linear cellulosic polymer, and their derivatives, or a combination thereof.

According to any one of the embodiments described herein, the linear oligosaccharide is selected from the group consisting of maltodextrin, raffinose, stachyose, fructo-oligosaccharide, or a combination thereof.

According to any one of the embodiments described herein, the linear polysaccharide is selected from the group consisting of starch and its derivatives, amylose, amylopectin, modified starch, carboxymethyl starch, glycogen, cellulose, hemicellulose, pectin, hydrocolloid, or a combination thereof.

According to any one of the embodiments described herein, the linear polymer is a carbomer, polycarbophil, polyvinyl alcohol, polyvinyl pyrrolidine, polyethylene glycol (PEG), hyaluronic acid (HA), cellulose derivative selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, hydroxy ethyl cellulose, or a combination thereof.

According to any one of the embodiments described herein, the precipitation inhibitor is sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose, and the solubilizing agent is methane sulfonic acid.

According to any one of the embodiments described herein, the composition further comprises a penetration enhancer.

According to any one of the embodiments described herein, the penetration enhancer is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of benzalkonium chloride, protamine sulfate, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), Palmitoyl tripeptide, Quil A, DMSO, EDTA, and sodium glycocholate, or a combination thereof.

According to any one of the embodiments described herein, the composition further comprises preservative, pH adjusting agent, or a combination thereof.

According to any one of the embodiments described herein, the preservative is present in an amount of about 0.001% to about 4% w/v and selected from the group consisting of benzalkonium chloride, biguanide compound, acylated amino acid, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, potassium sorbate, sodium borate, chlorhexidine digluconate, polyquad, perborate-based preservatives, mercuric compounds, and zinc polyol complexes, or a combination thereof.

According to any one of the embodiments described herein, the preservative is a biguanide compound selected from the group consisting of polyhexamethylene biguanide, alkyl-biguanide, polyoxyalkylene diamine biguanide or their water-soluble salt; 1,1'-hexamethylene-bis-{5-(4-chlorophenyl)-biguanide}; 1,1'-hexamethylene-bis-{5-(2-ethylhexyl) biguanide}, 1,1 '-hexamethylene-bis-{5-(4-fluoro phenyl)-biguanide}; (N,N"-bis(2-ethyl hexyl)-3, 12-diimino-2,4, 11, 13-tetraazatetra decanediimidamine, chlorhexidine or their salts, or a combination thereof.

According to any one of the embodiments described herein, the salts of biguanide compounds include but are not limited to hydrochloride, gluconate, digluconate, borate, acetate, sulphonate, tartrate, and citrate.

According to any one of the embodiments described herein, the preservative is polyhexamethylene biguanide or its salt.

According to any one of the embodiments described herein, the preservative is polyhexamethylene biguanide hydrochloride.

According to any one of the embodiments described herein, the preservative is acylated amino acid selected from a group consisting of acyl sarcosines or sarcosinates, acyl glutamates, acyl glycinates, acyl aspartates, acyl taurates, acyl malonates or acyl amino-malonates, their salts, or a combination thereof.

According to any one of the embodiments described herein, the acylated amino acid is N-lauroyl sarcosine sodium.

According to any one of the embodiments described herein, the composition comprises benzalkonium chloride, N-lauroyl sarcosine sodium, polyhexamethylene biguanide hydrochloride, or a combination thereof.

According to any one of the embodiments described herein, one or more pH-adjusting agent is an acid, an alkali metal salt, or a combination thereof.

According to any one of the embodiments described herein, the pH-adjusting agent is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof.

a tyrosine kinase inhibitor in an amount of about 0.01% to about 10% w/v selected from the group consisting of axitinib, sunitinib, lenvatinib, pazopanib, their isomers or salts thereof;
methane sulfonic acid in an amount of about 0.001% to about 30% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 30% w/v; and
water.

a tyrosine kinase inhibitor in an amount of about 0.01% to about 10% w/v selected from the group consisting of axitinib, sunitinib, lenvatinib, pazopanib, their isomers or salts thereof;
methane sulfonic acid in an amount of about 0.001% to about 30% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 30% w/v;
one or more preservative in an amount of about 0.001% to about 4% w/v selected from the group consisting of benzalkonium chloride, polyhexamethylene biguanide hydrochloride, N-lauroyl sarcosine sodium, or a combination thereof;
one or more pH adjusting agent in an amount of about 0.01% to about 5% w/v selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof; and
water.

a tyrosine kinase inhibitor in an amount of about 0.01% to about 10% w/v selected from the group consisting of axitinib, sunitinib, lenvatinib, pazopanib, their isomers or salts thereof;
methane sulfonic acid in an amount of about 0.001% to about 30% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 30% w/v;
one or more preservative in an amount of about 0.001% to about 4% w/v selected from the group consisting of benzalkonium chloride, polyhexamethylene biguanide hydrochloride, N-lauroyl sarcosine sodium, or a combination thereof;
one or more pH adjusting agent in an amount of about 0.01% to about 5% w/v selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof;
one or more penetration enhancer is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of benzalkonium chloride, protamine sulfate, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), Palmitoyl tripeptide, Quil A, DMSO, EDTA and sodium glycocholate, or a combination thereof, and
water.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof and the solubility enhancer ranges from about 1:0.5 to about 1:1000, preferably from about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:500, or most preferably from about 1:0.5 to about 1:100.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:50.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:20.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:35.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:3 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:16.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:4.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:1000, preferably from about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:500, or most preferably from about 1:0.5 to about 1:100.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:50.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:20.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:10.

According to any one of the embodiments described herein, the composition has one or more following characteristics:

molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10;
a pH in the range of about 6.0 to 8.0; or
an osmolality in the range of about 250 to 375 mOsml/kg.

According to any one of the embodiments described herein, the composition is useful to deliver a high concentration of a tyrosine kinase inhibitor in the posterior segment of the eye.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to about 5000 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to about 2500 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 50 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 100 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 200 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 300 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers a tyrosine kinase inhibitor in the posterior segment of the eye at a concentration at least 500 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.

According to any one of the embodiments described herein, the composition delivers tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of about 0.1 to about 1000 ng/gm.

According to any one of the embodiments described herein, the composition delivers tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of about 100 to about 300 ng/gm.

According to any one of the embodiments described herein, the composition delivers tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of about 190 ng/gm.

According to any one of the embodiments described herein, the posterior segment of the eye may include sclera, choroid, Bruch's membrane, retinal pigment epithelium (RPE), neural retina, and vitreous humor.

According to any one of the embodiments described herein, the posterior segment of eye may include retina, vitreous humor, sclera, RPE-Choroid, aqueous humor, and Iris-ciliary body.

According to any one of the embodiments described herein, the present invention provides an ophthalmic solution composition for use in the treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity.

According to any one of the embodiments described herein, the present invention provides use of a medicament prepared according to the present invention in the treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity by administering via ophthalmic route in mammals.

According to any one of the embodiments described herein, the salts of tyrosine kinase inhibitors, or their isomers are selected from mesylate, tosylate, besylate, or esylate.

In one particular embodiment, the present invention provides a topical pharmaceutical composition of axitinib.

In one embodiment, the present invention provides a topical pharmaceutical composition of axitinib for the prevention or treatment of a posterior eye disease.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver a high concentration of axitinib in the posterior segment of the eye.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC₅₀ value of the axitinib.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 8000 times higher than the IC₅₀ value of the axitinib.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 6000 times higher than the IC₅₀ value of the axitinib.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 4000 times higher than the IC₅₀ value of the axitinib.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 3000 times higher than the IC₅₀ value of the axitinib.

In another embodiment, the present invention provides a topical pharmaceutical composition to deliver axitinib in the posterior segment of the eye at a concentration of up to 2500 times higher than the IC₅₀ value of the axitinib.

In one embodiment, the present invention provides a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, and a solubility enhancer.

In one embodiment, the present invention provides a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, and one or more solubility enhancer.

In another embodiment, the composition further comprises one or more precipitation inhibitor.

In one embodiment, the present invention provides a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, one or more solubility enhancer, one or more precipitation inhibitor, one or more preservative, and one or more pH adjusting agent.

In one embodiment, the present invention provides a topical pharmaceutical composition comprising axitinib, its isomer, or a salt thereof, one or more solubility enhancer, one or more precipitation inhibitor, one or more preservative, one or more pH adjusting agent and one or more penetration enhancer.

In one particular embodiment, the present invention provides a topical pharmaceutical composition of axitinib, its isomer, or a salt thereof comprising:

one or more solubility enhancer;
one or more precipitation inhibitor;
optionally one or more penetration enhancer;
one or more preservative; and
one or more pH adjusting agent.

axitinib, its isomer, or a salt thereof from about 0.01% to about 10%;
one or more solubility enhancer from about 0.001% to about 30% w/v; and
one or more pharmaceutically acceptable excipient.

axitinib, its isomer, or a salt thereof from about 0.01% to about 10%;
one or more solubility enhancer from about 0.001% to about 30% w/v;
one or more precipitation inhibitor from about 0.05% to about 30%; w/v and
one or more pharmaceutically acceptable excipient.

axitinib, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v; and
one or more pharmaceutically acceptable excipient.

axitinib, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v;
one or more pharmaceutically acceptable excipient; and
water.

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v selected from the group consisting of organic acid, mineral acid, or a combination thereof;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof; and
one or more pharmaceutically acceptable excipient.

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v selected from the group consisting of organic acid, mineral acid, or a combination thereof;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof; and
one or more pharmaceutically acceptable excipient; and
water.

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 10% w/v;
methane sulfonic acid in an amount of about 0.001% to about 30% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 30% w/v; and
water.

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 10% w/v;
methane sulfonic acid in an amount of about 0.001% to about 30% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 30% w/v;
one or more preservative in an amount of about 0.001% to about 4% w/v selected from the group consisting of benzalkonium chloride, polyhexamethylene biguanide hydrochloride, N-lauroyl sarcosine sodium, or a combination thereof;
one or more pH adjusting agent in an amount of about 0.01% to about 5% w/v selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof; and
water.

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 10% w/v;
methane sulfonic acid in an amount of about 0.001% to about 30% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 30% w/v;
one or more preservative in an amount of about 0.001% to about 4% w/v selected from the group consisting of benzalkonium chloride, polyhexamethylene biguanide hydrochloride, N-lauroyl sarcosine sodium, or a combination thereof;
one or more pH adjusting agent in an amount of about 0.01% to about 5% w/v selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof;
one or more penetration enhancer is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of benzalkonium chloride, protamine sulfate, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), Palmitoyl tripeptide, Quil A, DMSO, EDTA and sodium glycocholate, or a combination thereof, and
water.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:1000, preferably from about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:500, or most preferably from about 1:0.5 to about 1:100.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:50.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:20.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:1 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:35.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:3 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:16.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:4.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof and the precipitation inhibitor ranges from about 1:0.5 to about 1:1000, preferably from about 1:0.5 to about 1:800, about 1:0.5 to about 1:700, about 1:0.5 to about 1:500, or most preferably from about 1:0.5 to about 1:100.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:50.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:20.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:0.5 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:0.5 to about 1:5.

According to any one of the embodiments described herein, the molar ratio between the axitinib and the methane sulfonic acid ranges from about 1:0.5 to about 1:3.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:2 to about 1:4.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:0.5 to about 1:50.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:0.5 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:0.5 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:0.5 to about 1:10.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the cyclodextrin ranges from about 1:1 to about 1:30.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:0.5 to about 1:50.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:0.5 to about 1:40.

According to any one of the embodiments described herein, the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:1 to about 1:30.

molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10;
a pH in the range of about 6.0 to 8.0; or
an osmolality in the range of about 250 to 375 mOsml/kg.

molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:0.5 to about 1:10;
a pH in the range of about 6.0 to 8.0; or
an osmolality in the range of about 250 to 375 mOsml/kg.

molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:0.5 to about 1:10;
a pH in the range of about 6.0 to 8.0; or
an osmolality in the range of about 250 to 375 mOsml/kg.

In one embodiment, the present invention relates to a topical pharmaceutical composition comprising:

about 0.01% to about 10% w/v axitinib; and
about 1% to about 20% w/v β-cyclodextrin derivatives such as SBEβCD.

In one embodiment, the present invention relates to a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v β-cyclodextrin derivatives such as SBEβCD and about 0.1% to about 2% w/v HPMC.

In one embodiment, the present invention relates to a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v β-cyclodextrin derivatives such as SBEβCD and about 0.1% to about 2% w/v HPMC, and about 0.05% to about 15%w/v polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer.

In one embodiment, the present invention relates to a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v β-cyclodextrin derivatives such as SBEβCD and about 0.1% to about 2% w/v HPMC, and about 0.001% to about 0.2% w/v benzalkonium chloride.

In one embodiment, the present invention relates to a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v β-cyclodextrin derivatives such as SBEβCD and about 0.1% to about 2% w/v HPMC, and about 0.1% to about 4% w/v boric acid.

In one embodiment, the present invention relates to a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v β-cyclodextrin derivatives such as SBEβCD and about 0.1% to about 2% w/v HPMC, and about 0.5% to about 5% w/v tromethamine.

In one embodiment, the present invention relates to a topical pharmaceutical composition comprising about 0.01% to about 10% w/v axitinib, about 1% to about 20% w/v β-cyclodextrin derivatives such as SBEβCD and about 0.1% to about 2% w/v HPMC and about 0.01% to 5% w/v protamine sulfate.

about 0.01% to about 10% w/v axitinib;
about 1% to about 20% w/v SBEβCD;
about 0.05% to about 15% w/v polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer;
about 0.1% to about 2% w/v HPMC;
about 0.001% to about 0.2% w/v benzalkonium chloride;
about 0.1% to about 4% w/v boric acid;
about 0.5% to about 5% w/v tromethamine; and
optionally about 0.01% to about 5% w/v protamine sulfate.

about 0.125% w/v axitinib;
about 5.525% w/v SBEβCD;
about 1% w/v polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer;
about 0.3% w/v HPMC;
about 0.02% w/v benzalkonium chloride;
about 1% w/v boric acid;
about 2.8% w/v tromethamine; and
optionally about 0.015% w/v protamine sulfate.

According to any one of the embodiments described herein, the composition has a pH in the range of about 4.5 to 8.5.

According to any one of the embodiments described herein, the composition has a pH in the range of about 5.0 to 8.0.

According to any one of the embodiments described herein, the composition has a pH in the range of about 6.0 to 8.0.

According to any one of the embodiments described herein, the composition has a pH in the range of about 6.5 to 7.5.

According to any one of the embodiments described herein, the composition has a pH in the range of about 6.0 to 7.1.

According to any one of the embodiments described herein, the composition has an osmolality in the range of about 150 to 450 mOsml/kg.

According to any one of the embodiments described herein, the composition has an osmolality in the range of about 250 to 375 mOsml/kg.

The viscosity of the composition according to the present invention ranges from about 2 cps to 1000 cps. Preferably the viscosity of the composition according to the present invention ranges from about 5 cps to 75 cps, more preferably from 5 cps to 30 cps such as for example 6, 7, 8, 9, 10, ii, 12, 13, 14, 15, 16, 17, 18, 19, 20, 60 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 cps or intermediate values thereof. In one embodiment, the viscosity is measured at 25° C with a Rheometer-type viscometer at a shear rate of 100 s^-1.

According to any one of the embodiments described herein, the composition has a viscosity in the range of about 5 to 30 cps.

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 10% w/v;
one or more solubility enhancer in an amount of about 0.001% to about 30% w/v selected from the group consisting of organic acid, mineral acid, or a combination thereof;
one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof; and
one or more pharmaceutically acceptable excipient; and
water;

wherein the composition has one or more following characteristics:

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 10% w/v;
methane sulfonic acid in an amount of about 0.001% to about 30% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 30% w/v;
one or more preservative in an amount of about 0.001% to about 4% w/v selected from the group consisting of benzalkonium chloride, polyhexamethylene biguanide hydrochloride, N-lauroyl sarcosine sodium, or a combination thereof;
one or more pH adjusting agent in an amount of about 0.01% to about 5% w/v selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof; and
water;

wherein the composition has one or more following characteristics:

molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:0.5 to about 1:5;
molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:0.5 to about 1:10;
a pH in the range of about 6.0 to 8.0; or
an osmolality in the range of about 250 to 375 mOsml/kg.

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 10% w/v;
methane sulfonic acid in an amount of about 0.001% to about 30% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 30% w/v;
one or more preservative in an amount of about 0.001% to about 4% w/v selected from the group consisting of benzalkonium chloride, polyhexamethylene biguanide hydrochloride, N-lauroyl sarcosine sodium, or a combination thereof;
one or more pH adjusting agent in an amount of about 0.01% to about 5% w/v selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof;
one or more penetration enhancer is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of benzalkonium chloride, protamine sulfate, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), Palmitoyl tripeptide, Quil A, DMSO, EDTA and sodium glycocholate, or a combination thereof, and
water;

wherein the composition has one or more following characteristics:

molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:0.5 to about 1:5;
molar ratio between the axitinib and the sulfobutyl ether β-cyclodextrin ranges from about 1:0.5 to about 1:10;
a pH in the range of about 6.0 to 8.0; or
an osmolality in the range of about 250 to 375 mOsml/kg.

axitinib, its isomer, or a salt thereof, in an amount of about 0.01% to about 5% w/v;
methane sulfonic acid in an amount of about 0.001% to about 10% w/v;
sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose in an amount of about 0.05% to about 20% w/v;
one or more preservative in an amount of about 0.001% to about 4% w/v selected from the group consisting of benzalkonium chloride, polyhexamethylene biguanide hydrochloride, N-lauroyl sarcosine sodium, or a combination thereof;
one or more pH adjusting agent in an amount of about 0.01% to about 5% w/v selected from the group consisting of boric acid, citric acid, tromethamine, and potassium phosphate, or a combination thereof;
one or more penetration enhancer is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of benzalkonium chloride, protamine sulfate, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), Palmitoyl tripeptide, Quil A, DMSO, EDTA and sodium glycocholate, or a combination thereof, and
water;

wherein the composition has one or more following characteristics:

In one embodiment, the present invention provides an ophthalmic solution composition comprising:

axitinib, its isomer, or a salt thereof;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
one or more pharmaceutically acceptable excipient; and
water.

axitinib, its isomer, or a salt thereof;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
one or more pharmaceutically acceptable excipient; and
water.

axitinib, its isomer, or a salt thereof in an amount of about 0.01% to about 5% w/v;
about 1% to about 20% w/v of sulfobutyl ether β-cyclodextrin;
about 0.05% to about 10% w/v of methane sulfonic acid;
one or more pharmaceutically acceptable excipient; and
water.

axitinib, its isomer, or a salt thereof in an amount of about 0.01% to about 5% w/v;
about 1% to about 20% w/v of sulfobutyl ether β-cyclodextrin;
about 0.05% to about 10% w/v of methane sulfonic acid;
about 0.1% to about 2% w/v of hydroxypropyl methyl cellulose;
one or more pharmaceutically acceptable excipient; and
water.

wherein the composition has one or more following characteristics:

molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:0.5 to about 1:20;
molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:0.5 to about 1:10;
a pH in the range of about 6.5 to 7.5; or
an osmolality in the range of about 250 to 375 mOsml/kg.

According to any one of the embodiments described herein, one or more excipient is selected from the group consisting of benzalkonium chloride, tromethamine, N-lauroyl sarcosine sodiums, boric acid, polyhexamethylene biguanide hydrochloride, Quil A, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), and Palmitoyl tripeptide.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
benzalkonium chloride;
tromethamine; and
water.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
benzalkonium chloride;
sodium N-lauroyl sarcosinate;
boric acid;
polyhexamethylene biguanide hydrochloride;
tromethamine; and
water.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
boric acid;
polyhexamethylene biguanide hydrochloride;
tromethamine; and
water.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
sodium N-lauroyl sarcosinate;
boric acid;
polyhexamethylene biguanide hydrochloride;
tromethamine; and
water.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
benzalkonium chloride;
boric acid;
polyhexamethylene biguanide hydrochloride;
tromethamine; and
water.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
benzalkonium chloride;
sodium N-lauroyl sarcosinate;
boric acid;
polyhexamethylene biguanide hydrochloride;
Quil A;
tromethamine; and
water.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
benzalkonium chloride;
sodium N-lauroyl sarcosinate;
boric acid;
polyhexamethylene biguanide hydrochloride;
salcaprozate sodium; and
water.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
benzalkonium chloride;
sodium N-lauroyl sarcosinate;
boric acid;
polyhexamethylene biguanide hydrochloride;
salcaprozate sodium;
tromethamine; and
water.

axitinib;
sulfobutyl ether β-cyclodextrin;
methane sulfonic acid;
hydroxypropyl methyl cellulose;
benzalkonium chloride;
sodium N-lauroyl sarcosinate;
boric acid;
polyhexamethylene biguanide hydrochloride;
perifosine;
tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8.8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.21% w/v of tromethamine; and
water.

about 0.3% w/v of axitinib;
about 9.2% w/v of sulfobutyl ether β-cyclodextrin;
about 0.23% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.3% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.06% w/v of sodium N-lauroyl sarcosinate;
about 0.45% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.28% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.5% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.27% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.06% w/v of sodium N-lauroyl sarcosinate;
about 0.5% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.27% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.5% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.29% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.3% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.22% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.4% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.26% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.06% w/v of sodium N-lauroyl sarcosinate;
about 0.45% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.05% w/v of Quil A;
about 0.22% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.06% w/v of sodium N-lauroyl sarcosinate;
about 0.45% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.05% w/v of n-dodecyl-beta-D-maltoside;
about 0.23% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.06% w/v of sodium N-lauroyl sarcosinate;
about 0.45% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.05% w/v of Palmitoyl tripeptide;
about 0.23% w/v of tromethamine; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.06% w/v of sodium N-lauroyl sarcosinate;
about 0.45% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.05% w/v of salcaprozate sodium; and
water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.06% w/v of sodium N-lauroyl sarcosinate;
about 0.45% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.05% w/v of perifosine;
about 0.23% w/v of tromethamine; and
water.

about 0.125% w/v of axitinib;
about 5.5% w/v of sulfobutyl ether β-cyclodextrin;
about 0.1% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.02% w/v of benzalkonium chloride;
about 1% w/v of boric acid;
about 2.8% w/v of tromethamine; and
water.

about 2.5% w/v of axitinib;
about 5.5% w/v of sulfobutyl ether β-cyclodextrin;
about 4% w/v of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer;
about 0.1% w/v of methane sulfonic acid;
about 0.02% w/v of benzalkonium chloride;
about 1% w/v of boric acid;
about 2.8% w/v of tromethamine; and
water.

about 0.3% w/v of axitinib;
about 9.2% w/v of sulfobutyl ether β-cyclodextrin;
about 0.23% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;
about 0.06% w/v of sodium N-lauroyl sarcosinate;
about 0.05% w/v of boric acid;
about 0.1% w/v of potassium sorbate;
about 0.25% w/v of tromethamine; and
water.

about 0.1% w/v of axitinib;
about 5% w/v of sulfobutyl ether β-cyclodextrin;
about 0.08% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;

about 0.9% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.20% w/v of tromethamine; and

water.

about 0.2% w/v of axitinib;
about 8% w/v of sulfobutyl ether β-cyclodextrin;
about 0.16% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;

about 0.5% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.29% w/v of tromethamine; and

water.

about 0.1% w/v of axitinib;
about 7% w/v of sulfobutyl ether β-cyclodextrin;
about 0.08% w/v of methane sulfonic acid;
about 0.3% w/v of hydroxypropyl methyl cellulose;
about 0.01% w/v of benzalkonium chloride;

about 0.5% w/v of boric acid;
about 0.02% w/v of polyhexamethylene biguanide hydrochloride;
about 0.20% w/v of tromethamine; and

water.

According to any one of the embodiments described herein, the ophthalmic solution compositions are stable.

The term “stable” refers to preparation as per the present invention having sufficient stability to allow storage at a convenient temperature and relative humidity such as 25°C and 60% R.H., 40°C and 75% and/or 2-8°C for a pharmaceutically acceptable duration of time. According to any one of the embodiments described herein, the ophthalmic solution compositions are stable for at least one day. According to any one of the embodiments described herein, the ophthalmic solution compositions are stable for at least about one week. According to any one of the embodiments described herein, the ophthalmic solution compositions are stable for one month. According to any one of the embodiments described herein, the ophthalmic solution compositions are stable for six months. According to any one of the embodiments described herein, the ophthalmic solution compositions are stable for about one month to about two years.

According to any one of the embodiments described herein, the composition is free from any organic solvent. According to any one of the embodiments described herein, the composition is free from alcohol.

According to any one of the embodiments described herein, the composition is not a suspension.

According to any one of the embodiments described herein, the composition is not an emulsion.

According to any one of the embodiments described herein, the composition is a single-phase solution.

According to any one of the embodiments described herein, the composition is a single-phase aqueous solution.

According to any one of the embodiments described herein, the composition is not a biphasic solution.

According to any one of the embodiments described herein, the composition does not comprise any undissolved particles.

According to any one of the embodiments described herein, the composition is not for administered as injection composition.

According to any one of the embodiments described herein, the composition is not for administered as an implant.

According to any one of the embodiments described herein, the composition is not injected into the suprachoroidal space (SCS) or subretinal space of an eye.

According to any one of the embodiments described herein, the composition is free from surfactant.

According to any one of the embodiments described herein, the composition is free from poloxamer.

According to any one of the embodiments described herein, the composition is free from polysorbate.

According to any one of the embodiments described herein, the composition is free from sorbitan monolaurate, poloxamer, and/or polysorbate.

According to any one of the embodiments described herein, the composition is free from poloxamer and/or polysorbate.

According to any one of the embodiments described herein, the composition is free of any chelating agent.

According to any one of the embodiments described herein, the composition is free of any chelating agent selected from the group consisting of edetate disodium, ethylenediamine tetraacetic acid (EDTA), edetic acid, disodium edetate dihydrate, and diethylenetriamine pentaacetic.

According to any one of the embodiments described herein, the composition is free of ethylenediamine tetraacetic acid (EDTA).

According to any one of the embodiments described herein, the composition comprises less than about 40% w/v of one or more solubility enhancer.

According to any one of the embodiments described herein, the composition comprises less than about 40% w/v of cyclodextrin derivatives.

According to any one of the embodiments described herein, the composition comprises less than about 40% w/v of cyclodextrin derivatives selected from the group consisting of 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD) and 2-hydroxypropyl-γ-cyclodextrin, or a combination thereof.

According to any one of the embodiments described herein, the composition comprises less than about 40% w/v of sulfobutyl ether β-cyclodextrin (SBEβCD).

According to any one of the embodiments described herein, the composition is free of γ-cyclodextrin and any chelating agent.

According to any one of the embodiments described herein, the composition is free of any stabilizer selected from the group consisting of adenine, guanine, caffeine, theobromine, isoguanine, xanthine, hypoxanthine, uric acid, any combination thereof, etc.

According to any one of the embodiments described herein, the composition is free of caffeine.

According to any one of the embodiments described herein, the composition is useful to deliver a high concentration of axitinib in the posterior segment of the eye.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration of up to 10000 times higher than the IC₅₀ value of axitinib.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration of up to about 5000 times higher than the IC₅₀ value of the axitinib.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration of up to about 2500 times higher than the IC₅₀ value of axitinib.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 50 times higher than the IC₅₀ value of axitinib.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 100 times higher than the IC₅₀ value of axitinib.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 200 times higher than the IC₅₀ value of axitinib.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 300 times higher than the IC₅₀ value of axitinib.

According to any one of the embodiments described herein, the topical pharmaceutical composition delivers axitinib in the posterior segment of the eye at a concentration at least 500 times higher than the IC₅₀ value of axitinib.

According to any one of the embodiments described herein, the composition delivers axitinib in the posterior segment of the eye at a concentration of about 0.1 to about 1000 ng/gm.

According to any one of the embodiments described herein, the composition delivers axitinib in the posterior segment of the eye at a concentration of about 100 to about 300 ng/gm.

According to any one of the embodiments described herein, the composition delivers axitinib in the posterior segment of the eye at a concentration of about 190 ng/gm.

According to any one of the embodiments described herein, the salts of axitinib or their isomers are selected from mesylate, tosylate, besylate, or esylate.

According to any one of the embodiments described herein, the composition contains axitinib as the sole active ingredient.

According to any one of the embodiments described herein, axitinib is present in the free base form.

In one embodiment, the present invention provides a process for the preparation of a pharmaceutical composition according to any one of the embodiments described herein.

In one embodiment, the process for the preparation of a pharmaceutical composition comprising:

dissolving a solubility enhancer in water for injection;
adding an active pharmaceutical ingredient;
optionally adding another solubilizing enhancer;
adding a precipitation inhibitor under stirring;
adding one or more preservative;
adjusting pH of the solution; and
adding water for injection to adjust volume.

dissolving a solubility enhancer in water for injection;
adding a tyrosine kinase inhibitor;
optionally adding another solubilizing enhancer;
adding a precipitation inhibitor under stirring;
adding one or more preservative;
adjusting pH of the solution; and
adding water for injection to adjust volume.

dissolving one or more suitable precipitation inhibitor in water under continuous stirring to obtain a homogenous dispersion;
making the volume with water and autoclaving it to make it sterile;
separately dissolving one or more suitable pH adjusting agent, and preservatives in water under continuous stirring to obtain a clear solution;
dissolving one or more solubility enhancer in water under continuous stirring; adding drug; optionally heating to a suitable temperature (about 30-60°C) and optionally adding one or more solubility enhancer under continuous stirring to obtain a clear solution;
adding step c) solution to step b) solution and passing through a suitable filter;
adding step d) solution to step e) solution and passing through a suitable filter to obtain a homogenous solution;
optionally adding penetration enhancers to step f) and passing through a suitable filter
making the volume with water and passing the solution through a suitable filter;
filling the solution into a suitable bottle with pre and post nitrogen purging and plugging with a suitable closure.

Preparation of polymer phase: Taking the required quantity of water for injection in a vessel. Adding suitable precipitation inhibitor slowly into vehicle maintaining at a suitable temperature of about 70-90°C using an overhead stirrer. Continue the stirring to obtain a homogeneous dispersion. Maintain the temperature throughout the preparation. Decreasing the temperature once homogeneous dispersion is formed to room temperature and continue the stirring. Making the total volume to the mark with water for injection and autoclaving the phase to make it sterile.
Preparation of vehicle phase: Taking required quantity of vehicle in a vessel or glass vial. Adding suitable excipients (such as pH adjusting agent(s), preservative(s)). Stirring the solution after the addition of each excipient and dissolving till a clear solution forms.
Preparation of drug phase: Taking filtered water for injection in a vessel or glass bottle and adding solubilizing agent to this and stirring. Adding the drug followed by the addition of vehicle. Heating to a suitable temperature of about 40-50℃ and stirring. Adding precipitation inhibitor to the above solution and keeping under stirring at a suitable temperature of about 40-50 ℃ till it becomes a clear solution.
Preparation of bulk solution: Adding clear vehicle phase solution to the sterile autoclaved polymer phase by passing through a suitable filter (0.2-micron sterile grade filter). Stirring the solution to ensure sufficient mixing. Adding drug phase solution to the above polymer-vehicle mixed phase by passing through a suitable filter (0.2-micron sterile grade filter). Stirring the solution to ensure sufficient mixing. Making the volume to the desired batch size. Filtering the bulk solution through a suitable filter (40 micron polishing filter).
Filling: Filling the filtered solution in a suitable bottle with nitrogen purging, plugged, and capped with a tamper-proof closure.

Addition of precipitation inhibitor was found to be crucial for obtaining a stable solution. Inventor observed that the drug when dissolved in the vehicle with the help of a solubilizing agent tends to precipitate during further processing of the composition at the time of addition of other excipients. This resulted in failed batches. Various experiments were performed to overcome the problem. The present inventor found that the addition of one or more precipitation inhibitor is required to prevent the precipitation of the drug and to obtain a stable composition. In the first experiment, inventor prepared a solution composition of axitinib by adding a solubilizing agent (methane sulfonic acid) in water, followed by the addition of drug (axitinib). However, the drug was precipitated upon addition of pH adjusting agent (tromethamine). In the second experiment, inventor prepared a solution composition of axitinib by adding a solubilizing agent (methane sulfonic acid) in water followed by the addition of drug (axitinib). Precipitation inhibitors (SBEβCD and HPMC) were added to the above solution. No precipitation was observed at the time of pH adjustment using a pH adjusting agent (tromethamine). In the third experiment, inventor prepared a solution composition of axitinib by adding a precipitation inhibitor (SBEβCD) in water followed by the addition of drug (axitinib). Solubilizing agent (methane sulfonic acid) was added to the above solution to make a clear yellow solution. No precipitation was observed at the time of pH adjustment using a pH adjusting agent (tromethamine).

Preparation of polymer phase: Taking the required quantity of water for injection in a vessel. Adding Hydroxypropyl methylcellulose slowly into water for injection maintaining at a suitable temperature of about 70-90°C using an overhead stirrer. Continue the stirring to obtain a homogeneous dispersion. Maintain the temperature throughout the preparation. Decreasing the temperature once homogeneous dispersion is formed to room temperature and continue the stirring. Making the total volume to the mark with water for injection and autoclaving the phase to make it sterile.
Preparation of vehicle phase: Taking required quantity of water for injection in a vessel or glass vial. Adding excipients (such as boric acid, benzalkonium chloride, Polyhexamethylene biguanide hydrochloride, Sodium N-lauroyl sarcosinate, tromethamine). Stirring the solution after the addition of each excipient and dissolving till a clear solution forms.
Preparation of drug phase: Taking filtered water for injection in a vessel or glass bottle and adding methane sulfonic acid to this and stirring. Adding the drug followed by the addition of water for injection. Heating to a suitable temperature of about 40-50℃ and stirring. Adding SBEβCD to the above solution and keeping under stirring at a suitable temperature of about 40-50 ℃ till it becomes a clear solution.
Preparation of bulk solution: Adding clear vehicle phase solution to the sterile autoclaved polymer phase by passing through a suitable filter (0.2-micron sterile grade filter). Stirring the solution to ensure sufficient mixing. Adding drug phase solution to the above polymer-vehicle mixed phase by passing through a suitable filter (0.2-micron sterile grade filter). Stirring the solution to ensure sufficient mixing. Making the volume to the desired batch size. Filtering the bulk solution through a suitable filter (40 micron polishing filter).
Filling: Filling the filtered solution in a suitable bottle with nitrogen purging, plugged, and capped with a tamper-proof closure.

Preparation of polymer phase: Taking the required quantity of water for injection in a vessel. Adding Hydroxypropyl methylcellulose slowly into the vortex of vigorously agitated water for injection maintaining at a suitable temperature of about 70-90°C using an overhead stirrer. Continue the stirring to obtain a homogeneous dispersion. Maintain the temperature throughout the preparation. Decreasing the temperature once homogeneous dispersion is formed to room temperature and continue the stirring. Making the total volume to the mark with water for injection and autoclaving the phase to make it sterile.
Preparation of vehicle phase: Taking required quantity of water for injection in a vessel or glass vial. Adding excipients (such as boric acid, benzalkonium chloride, Polyhexamethylene biguanide hydrochloride, Sodium N-lauroyl sarcosinate, tromethamine). Stirring the solution after the addition of each excipient and dissolving till a clear solution forms.
Preparation of drug phase: Taking filtered water for injection in a vessel or glass bottle and adding methane sulfonic acid to this and stirring. Adding the drug followed by the addition of water for injection. Heating to a suitable temperature of about 40-50℃ and stirring. Adding SBEβCD to the above solution and keeping under stirring at a suitable temperature of about 40-50 ℃ till it becomes a clear solution.
Bulk solution Preparation: Adding previously prepared clear vehicle phase solution to the sterile autoclaved polymer phase by passing through a suitable filter (0.2-micron sterile grade filter). Taking filtered water for injection in a vessel or glass vial and adding the following excipients based on their presence in formula (Quil-A, SNAC, Perifosine, N-Dodecyl-Beta-D-Maltoside, Palmitoyl tripeptide). Stirring the solution to ensure sufficient mixing. Passing through a suitable filter (0.2-micron sterile grade filter) to previously prepared sterile autoclaved solution containing vehicle phase. Adding drug phase solution to the above polymer-vehicle mixed phase by passing through a suitable filter (0.2-micron sterile grade filter). Stirring the solution to ensure sufficient mixing. Making the volume to the desired batch size. Filtering the bulk solution through a suitable filter (40 µ micron polishing filter).
Filling: Filling the filtered solution in a suitable bottle with nitrogen purging, plugged, and capped with a tamper-proof closure.

According to any one of the embodiments described herein, one or more solubility enhancer is an acid selected from the group consisting of organic acid, mineral acid, or a combination thereof. According to any one of the embodiments described herein, the organic acid is alkyl sulfonic acid. Alkyl sulfonic acid may include methane sulfonic acid, butane sulfonic acid, propane sulfonic acid, or a combination thereof. An organic acid is an organic compound with acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group –COOH. Sulfonic acids, containing the group –SO2OH, are relatively stronger acids. Alcohols, with –OH, can act as acids but they are usually very weak. The relative stability of the conjugate base of the acid determines its acidity. Other groups can also confer acidity, usually weakly: the thiol group –SH, the enol group, and the phenol group. In biological systems, organic compounds containing these groups are generally referred to as organic acids. Organic acid as per the present invention may include cinnamaldehyde, acetic acid, propionic acid, butanoic acid, benzoic acid, mandelic acid, fumaric acid, sorbic acid, boric acid, succinic acid, adipic acid, glycolic acid, glutaric acid, butyric acid, folic acid, or a combination thereof. A mineral acid (or inorganic acid) is an acid derived from one or more inorganic compounds, as opposed to organic acids which are acidic, organic compounds. All mineral acids form hydrogen ions and the conjugate base when dissolved in water. Mineral acid may include solutions of a hydrogen halide, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, perchloric acid, hydrogen cyanide, or a combination thereof. Preferred mineral acid may include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, sulfamic acid, or a combination thereof. The composition may include any other pharmaceutically acceptable compounds or excipients capable of solubility enhancement. One or more solubility enhancer is present in an amount from about 0.001% to about 50% w/v, preferably from about 0.001% to about 40% w/v. In one embodiment, one or more solubility enhancer is present in an amount from about 0.001% to about 30% w/v. For example, about 0.44%, about 5.525%, about 4.9%, about 10%, about 15%, about 20%, about 25%, or about 30% w/v.

A "precipitation inhibitor" in pharmaceuticals refers to an excipient, added to a drug formulation to prevent the drug from precipitating out of solution, to enhance its absorption and bioavailability. Precipitation inhibitors include, but not limited to, cyclic polymer, linear polymer, or a combination thereof. Cyclic polymers are a relatively uncommon class of macromolecules with a ring-like architecture with repeating units of monomers. Cyclic polymer includes cyclic oligosaccharide, cyclic polysaccharide, cyclic non-oligosaccharides, or a combination thereof.

As used herein, the term "cyclic oligosaccharide" means macromolecules with ring-like architecture formed of 3-10 monosaccharides bound together by glycosidic linkages. Cyclic oligosaccharide may include cyclosophoran, cycloamylose, cyclic nigerosyl-1,6-nigerose (CNN), cyclotetraglucose, or cyclodextrins. The preferred cyclic oligosaccharides for use herein are cyclodextrins. Cyclic oligosaccharide include cyclosophoran, cycloamylose, cyclotetraglucose, cyclodextrin derivative selected from the group consisting of 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD), 2-hydroxypropyl-γ-cyclodextrin, methyl-β-cyclodextrin, carboxymethyl β-cyclodextrin. Cyclic polysaccharide is macromolecule with ring like architecture formed of more than 10 monosaccharide units bound together by glycosidic linkages. Cyclic polysaccharide includes cyclic β-1,2-glucan (CβG). Cyclic non-oligosaccharide is macromolecule with ring like architecture formed repeating units of moieties other than monosaccharides. Cyclic non-oligosaccharide is selected from the group consisting of cyclo poly(styrene), cyclo-poly(lactide), cyclo poly(ε-caprolactone) (PCL), cyclo poly(ethylene oxide) (PEO), or a combination thereof.

Linear polymer includes macromolecular chain in which all structural units or monomers exist in a single line with no branches or intramolecular bridges. Linear polymer includes, but not limited to, linear oligosaccharide, linear polysaccharide, linear cellulosic polymer, and their derivatives, or a combination thereof. Linear oligosaccharide is an oligosaccharide with a straight chain of (3-10) monosaccharides without any branching. Linear oligosaccharide include maltodextrin, raffinose, stachyose, fructo-oligosaccharide, galacto-oligosaccharide, or a combination thereof. Raffinose is a trisaccharide having formula C₁₈H₃₂O₁₆ formed with three sugar units, fructose, glucose, and galactose. Fructo-oligosaccharides are short chains of fructose residues. Galacto-oligosaccharides are made up of galactose molecules. Linear polysaccharide include macromolecules with a straight chain of more than 10 monosaccharides without any branching. Linear polysaccharide include starch and its derivatives, amylose, amylopectin, modified starch (esterified starch, carboxymethyl starch, pregelatinized starch, acetylated starch, etc.), carboxymethyl starch, glycogen, galactogen, cellulose, hemicellulose, pectin, hydrocolloid, or a combination thereof. Hydrocolloid is a mixture in which one substance consisting of microscopically dispersed insoluble particles is suspended throughout another substance. Hydrocolloids describe certain chemicals (mostly polysaccharides and proteins) that are colloidally dispersible in water. One or more hydrocolloid may include polyvinyl pyrrolidones, starch, polysaccharides, cellulose and cellulose derivatives, and mixtures thereof. The
polysaccharide may include one or more of alginic acid, sodium alginate, and calcium alginate. Linear cellulosic polymer includes cellulose which is an organic compound with the formula (C₆H₁₀O₅)n, a polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units. Preferred, linear polymer include carbomer, polycarbophil, polyvinyl alcohol, polyvinyl pyrrolidine, polyethylene glycol (PEG), hyaluronic acid (HA), cellulose derivative selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, hydroxy ethyl cellulose, or a combination thereof. In some embodiments, the precipitation inhibitors can also act as viscosity-regulating agent. In some embodiments, the precipitation inhibitor is a polymer. Preferably, the precipitation inhibitor is sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose. The composition may include any other pharmaceutically acceptable compounds or excipients capable of inhibiting the precipitation. One or more precipitation inhibitor are present in an amount from about 0.001% to about 50% w/v, preferably from about 0.001% to about 40% w/v. In one embodiment, one or more precipitation inhibitor is present in an amount from about 0.05% to about 30% w/v. For example, about 0.44%, about 5.525%, about 4.9%, about 10%, about 15%, about 20%, about 25%, or about 30% w/v.

One or more preservative is selected from boric acid, benzalkonium chloride, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, potassium sorbate, sodium borate, chlorhexidine digluconate, EDTA, polyquad, purite, perborate-based preservatives, other mercuric compounds, zinc polyol complexes, Poly Hexa-Methylene Biguanide (PHMB) or mixtures thereof. More preferably, the preservative is benzalkonium chloride, boric acid, or a combination thereof. In a preferred embodiment, one or more preservative is selected from the group consisting of benzalkonium chloride, biguanide compound, acylated amino acid, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, chlorhexidine digluconate, polyquad, perborate-based preservatives, mercuric compounds, and zinc polyol complexes or a combination thereof, or any other pharmaceutically acceptable compounds or excipients capable of maintaining the preservative efficacy. The preservatives are present in an amount from about 0.001% to about 10% w/v, preferably about 5% w/v. For example, about 0.1%, about 0.3%, about 1%, about 2% or about 5% w/v.

One or more pH adjusting agent is selected from pharmaceutically acceptable buffer systems such as citrate buffer, tartrate buffer, phosphate buffer, acetate buffer, lactate buffer, glycine buffer, or a mixture thereof, or any other pharmaceutically acceptable compounds or excipients capable of maintaining the pH. These include buffers containing any of the commonly used compounds or a combination of compounds such as citric acid, ascorbic acid, gluconic acid, carbonic acid, succinic acid, sodium citrate, potassium citrate, tartaric acid, sodium tartrate, phosphoric acid, methane sulfonic acid, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, acetic acid, phthalic acid, sodium acetate, lactic acid, sodium lactate, sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, disodium succinate hexahydrate, Tris, and tromethamine. Preferably, the pH-adjusting agent is tromethamine. In one preferred embodiment, one or more preservative is selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine and potassium phosphate or a combination thereof. One or more pH adjusting agent is present in an amount from about 0.001% to about 10% w/v, preferably about 5% w/v. For example, about 0.5%, about 0.1%, about 1%, about 2%, about 3%, about 4%, about 5% w/v.

The osmotic/tonicity adjusting agents may be selected from propylene glycol, glycerol, sodium chloride, potassium chloride, sodium bromide, calcium chloride, mannitol, sorbitol, dextrose, sucrose, mannose and the like and mixtures thereof, or any other pharmaceutically acceptable compounds or excipients capable of maintaining the tonicity. The compositions as per the present invention have osmolality in the range of about 150 to 450 mOsml/kg, preferably from about 250 to 375 mOsml/kg, preferably 270-350 mOsml/kg, such as for example 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340 or 345 mOsml/kg.

Suitable pharmaceutically acceptable vehicles include but are not limited to oleoyl polyethyleneglycol gylcerides, linoleoyl polyethyleneglycol gylcerides, lauroyl polyethyleneglycol gylcerides, hydrocarbon vehicles like liquid paraffin (Paraffinum liquidum, mineral oil), light liquid paraffin (low viscosity paraffin, Paraffinum perliquidum, light mineral oil), soft paraffin (vaseline), hard paraffin, vegetable fatty oils like castor oil, peanut oil or sesame oil, synthetic fatty oils like middle chain triglycerides (MCT, triglycerides with saturated fatty acids, preferably octanoic and decanoic acid), isopropyl myristate, caprylocaproyl macrogol-8 glyceride, caprylocaproyl polyoxyl-8 glycerides, wool alcohols like cetylstearylalcohols, wool fat, glycerol, propylene glycol, propylene glycol diesters of caprylic/capric acid, polyethylene glycols (PEG), water like an aqueous isotonic sodium chloride solution or a combination thereof. Preferably the ophthalmic composition comprises water. In one embodiment the composition comprises at least 99% by weight of water, at least 90% by weight of water, at least 95% by weight of water, or at least 98% by weight of water based on the total weight or volume of the composition. For example, the aqueous medium includes purified water, water for injection, sterile distilled water, and so on. The suitable vehicles/diluents include water, water for injection, purified water, Ringer's solution, and normal saline solution. In some embodiments, the term water is interchangeable with water for injection (WFI) and/or purified water and/or sterile water. In a preferred embodiment, the term water means Water for Injection (WFI).

According to any one of the embodiments described herein, the topical pharmaceutical composition is useful to treat, prevent, reduce, alleviate, or slow the progression or development of a disease such as posterior eye disease including but not limited to age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membrane (CNVM), cystoid macula edema (CME), epi-retinal membrane (ERM) and macular hole, myopia-associated choroidal neovascularization, vascular streaks, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes of the retinal pigment epithelium (RPE), hypertrophic changes of the retinal pigment epithelium (RPE), retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retinal vein occlusion, retinitis pigmentosa, Stargardt's disease, Myopic Choroidal Neovascularization (mCNV), and retinopathy of prematurity. Preferred posterior eye diseases include age-related macular degeneration (AMD) like dry AMD, wet AMD, or choroidal neovascularization (CNV). Examples of age-related macular degeneration (AMD) include but are not limited to dry or nonexudative AMD, or wet or exudative or neovascular AMD. Preferably, the topical pharmaceutical composition is useful for the treatment or prevention of age-related macular degeneration (AMD), diabetic macular edema (DME), Myopic Choroidal Neovascularization (mCNV), and/or diabetic retinopathy.

According to any one of the embodiments described herein, the pharmaceutical composition is suitable for administration to an animal or human.

EXAMPLES

Topical corneal permeability, distribution in posterior segment and safety pharmacology study in Rabbits for axitinib composition as per example 1:

The aim of this study was to determine whether topical ophthalmic administration (eye drops) of tyrosine kinase inhibitors of the present invention result in Corneal permeability, distribution, and safety pharmacology of active ingredient in the posterior segment of the eye.

For this purpose, New Zealand white Rabbits (Male and female) with no visible signs of ocular defects were selected. Animals were divided into two groups as described in below table:

Groups	n	Dosing details
Group 1	3 rabbits (6 eyes)	7-day dosing
Group 2	3 rabbits (6 eyes)	1-day dosing

The rabbits were restrained and were allowed to stabilize for 5-10 min before dosing. After that, they were administered axitinib (1.25 mg/ml) four times at approximately 3-4 hours intervals daily.

Various tissues of the eye (Retina, Posterior eye cup (RPE/choroid and sclera), vitreous humor)) and plasma were collected on day 8 after 1 h of the first dose. Aqueous humor was also collected from 3 eyes 30 min after the topical administration and from the remaining three eyes 1 h after the topical instillation of the first dose on day 8 in Group 1.

Upon measurements in all tissues, it was observed that in all groups, sufficient concentration of axitinib was present in all tissues and aqueous humor. Also, all the groups were found to be safe and tolerable as conclusive based on the data as mentioned in below table:

Tissue	Average concentration of Axitinib (ng/gm)	Standard Deviation
Conjunctiva	960.2	1019.4
Sclera	901.6	816.8
Choroid-Retina	287.9	53.6
Cornea	649.1	214.8
Iris	BQL
Lens	BQL
Aqueous humor	22.9	14.0

Limit of quantification 10 ng/ml, BQL: Below quantification limit

In conclusion, axitinib was well-distributed in target tissue choroid-retina with a concentration of 287.9 ng/gm of tissue and thus it is ~3700 fold higher than IC₅₀ of axitinib (0.077 ng/mL).

Likewise, the concentration of sunitinib, lenvatinib, and pazopanib in choroid-retina was at least 100 times higher than the IC₅₀ of the respective drug.

Example 1:

Preparation of ophthalmic solution containing axitinib:

Axitinib Eye Drops
Excipient	Each mL contains	% w/v
Axitinib	1.25 mg	0.125
SBEβCD	55.25 mg	5.525
HPMC F4M	3 mg	0.3
Methane sulfonic acid	1 mg	0.1
Benzalkonium chloride	0.2 mg	0.02
Boric acid	10 mg	1
Protamine sulfate	0.15 mg	0.015
Tromethamine	28 mg	2.8
Water for injection	q.s.	q.s.

SBEβCD was dissolved in water for injection. Weighed quantity of the axitinib was transferred to the vial containing SBEβCD solution and axitinib was solubilized by sonication and addition of methane sulfonic acid (axitinib:SBEβCD = 1:12). HPMC was added under continuous stirring. Consequently, boric acid solution was added under continuous stirring. Benzalkonium chloride was added under continuous stirring followed by addition of protamine sulfate under continuous stirring. pH was measured and adjusted using tromethamine solution to 5.5. Volume was made up using water for injection.

Example 1a:

Preparation of ophthalmic solution containing axitinib:

Axitinib Eye Drops
Excipient	Each mL contains	% w/v
Axitinib	1.25 mg	0.125
SBEβCD	55.25 mg	5.525
HPMC F4M	3 mg	0.3
Methane sulfonic acid	1 mg	0.1
Benzalkonium chloride	0.2 mg	0.02
Boric acid	10 mg	1
Tromethamine	28 mg	2.8
Water for injection	q.s.	q.s.

SBEβCD was dissolved in water for injection. Weighed quantity of the axitinib was transferred to the vial containing SBEβCD solution and axitinib was solubilized by sonication and addition of methane sulfonic acid (axitinib:SBEβCD = 1:12). HPMC was added under continuous stirring. Consequently, boric acid solution was added under continuous stirring. Benzalkonium chloride was added under continuous stirring. pH was measured and adjusted using tromethamine solution to 5.5. Volume was made up using water for injection.

Example 1b:

Preparation of ophthalmic solution containing axitinib:

Axitinib Eye Drops
Excipient	Each mL contains	% w/v
Axitinib	25 mg	2.5
SBEβCD	55.25 mg	5.525
Soluplus	40 mg	4
Methane sulfonic acid	1 mg	0.1
Benzalkonium chloride	0.2 mg	0.02
Boric acid	10 mg	1
Tromethamine	28 mg	2.8
Water for injection	q.s.	q.s.

SBEβCD was dissolved in water for injection. Weighed quantity of the axitinib was transferred to the vial containing SBEβCD solution and axitinib was solubilized by sonication and addition of methane sulfonic acid. Methane sulfonic acid was added under continuous stirring. Consequently, boric acid solution was added under continuous stirring. Benzalkonium chloride was added under continuous stirring. pH was measured and adjusted using tromethamine solution to 5.5. Volume was made up using water for injection.

The Example 1b composition delivers axitinib in the posterior segment of the eye at a concentration of about 190 ng/gm in Choroid-Retina. Upon measurements in all tissues, it was observed that in all groups, sufficient concentration of Axitinib was present in all tissues. Also, all the groups were found to be safe and tolerable as conclusive based on the data as mentioned in below table:

Tissue	Average concentration of Axitinib (ng/gm)	Standard Deviation
Conjunctiva	960.2	882.868
Sclera	514.75	562.5517
Choroid-Retina	190.25	111.0289
Cornea	649.1	186.0317
Iris	89.6	14.22252
Lens	61.45	6.69384

In conclusion, axitinib was well-distributed in target tissue choroid-retina with concentration of 190 ng/gm of tissue and thus it is ~2400 fold higher than IC₅₀ of Axitinib (0.077 ng/mL).

Example 2:

Preparation of ophthalmic solution containing lenvatinib:

Lenvatinib Eye Drops
Excipient	Each mL contains	% w/v
Lenvatinib mesylate	2 mg	0.2
SBEβCD	40.05 mg	4
HPMC F4M	3 mg	0.3
Methane sulfonic acid	1 mg	0.1
Benzalkonium chloride	0.2 mg	0.02
Boric acid	10 mg	1
Protamine sulfate	0.15 mg	0.015
Tromethamine	76 mg	7.6
Water for injection	q.s.	q.s.

SBEβCD was dissolved in water for injection. Weighed quantity of the lenvatinib was transferred to the vial containing SBEβCD solution and lenvatinib was solubilized by sonication and addition of methane sulfonic acid (lenvatinib: SBEβCD = 1:6). HPMC was added under continuous stirring. Consequently, boric acid solution was added under continuous stirring. Benzalkonium chloride was added under continuous stirring followed by addition of protamine sulfate under continuous stirring. pH was measured and adjusted using tromethamine solution to 5.5. Volume was made up using water for injection.

Example 3:

Preparation of ophthalmic solution containing sunitinib:

Sunitinib Eye Drops
Excipient	Each mL contains	% w/v
Sunitinib malate	4 mg	0.4
SBEβCD	43.71 mg	0.44
HPMC F4M	3 mg	0.3
Methane sulfonic acid	1 mg	0.1
Benzalkonium chloride	0.2 mg	0.02
Boric acid	10 mg	0.1
Protamine sulfate	0.15 mg	0.015
Tromethamine	60.8 mg	6
Water for injection	q.s.	q.s.

SBEβCD was dissolved in water for injection. Weighed quantity of the sunitinib was transferred to the vial containing SBEβCD solution and sunitinib was solubilized by heating (sunitinib:SBEβCD = 1:3). HPMC was added under continuous stirring. Consequently, boric acid solution was added under continuous stirring. Benzalkonium chloride was added under continuous stirring followed by addition of protamine sulfate. pH was measured and volume was made up using water for injection.

Example 4:

Preparation of ophthalmic solution containing pazopanib:

Pazopanib Eye Drops
Excipient	Each mL contains	% w/v
Pazopanib HCl	2.5 mg	0.25
SBEβCD	48.86 mg	4.9
HPMC F4M	3 mg	0.3
Methane sulfonic acid	1 mg	0.1
Benzalkonium chloride	0.2 mg	0.02
Boric acid	10 mg	1
Protamine sulfate	0.15 mg	0.015
Tromethamine	28 mg	2.8
Water for injection	q.s.	q.s.

SBEβCD was dissolved in water for injection. Weighed quantity of the pazopanib was transferred to the vial containing SBEβCD solution and pazopanib was solubilized by sonication and addition of methane sulfonic acid (pazopanib:SBEβCD = 1:6). HPMC was added under continuous stirring. Consequently, boric acid solution was added under continuous stirring. Benzalkonium chloride was added under continuous stirring followed by addition of protamine sulfate under continuous stirring. pH was measured and adjusted using tromethamine solution to 5.5. Volume was made up using water for injection.

Example 5:

Preparation of ophthalmic solution containing axitinib:

Ingredients	Quantity (% w/v)
Axitinib	0.2
SBEβCD	8
Methane sulfonic acid	0.16
Hydroxypropyl methylcellulose	0.3
Benzalkonium chloride	0.01
Sodium N-lauroyl sarcosinate	0.06
Boric acid	0.45
Polyhexamethylene biguanide hydrochloride	0.02
Tromethamine	0.28
Water for Injection (WFI)	q.s.

The prepared composition successfully achieved desired technical attributes as represented below:

S. No.	Tests	Results
1	pH	6.9
2	Osmolality (mOsml/kg)	320
3	Antimicrobial Effectiveness Test (AET)	Complies

Example 6-8:

Preparation of ophthalmic solutions containing axitinib:

Ingredients	6	7	8
Ingredients	Quantity (% w/v)
Axitinib	0.2	0.2	0.2
SBEβCD	8	8	8
Methane sulfonic acid	0.16	0.16	0.16
Hydroxypropyl methylcellulose	0.3	0.3	0.3
Benzalkonium chloride	-	-	0.01
Sodium N-lauroyl sarcosinate	-	0.06	-
Boric acid	0.5	0.5	0.5
Polyhexamethylene biguanide hydrochloride	0.02	0.02	0.02
Tromethamine	0.27	0.27	0.29
Water for Injection (WFI)	q.s.	q.s.	q.s.

S. No.	Tests	Results
S. No.	Tests	Ex. 6	Ex. 7	Ex. 8
1	pH	6.9	6.9	6.9
2	Osmolality (mOsml/kg)	332	340	337
3	Viscosity	-	-	13.12 cP
4	Antimicrobial Effectiveness Test (AET)	Complies	Complies	Complies
5	Drug Assay (Initial)	-	-	100.1
6	Drug Assay (1 month) 2-8°C	-	-	99.8
7	Drug Assay (1 month) 25°C/40% RH	-	-	99.5
8	Drug Assay (1 month) 40°C/25%RH	--	-	100.4

Example 9-10:

Preparation of ophthalmic solutions containing axitinib:

Ingredients	9	10
Ingredients	Quantity (% w/v)
Axitinib	0.2	0.2
SBEβCD	8	8
Methane sulfonic acid	0.16	0.16
Hydroxypropyl methylcellulose	0.3	0.3
Boric acid	0.3	0.4
Polyhexamethylene biguanide hydrochloride	0.02	0.02
Tromethamine	0.22	0.26
Water for Injection (WFI)	q.s.	q.s.

S. No.	Tests	Results
S. No.	Tests	Ex. 9	Ex. 10
1	pH	7.0	6.9
2	Osmolality (mOsml/kg)	317	334

Example 11-13:

Ingredients	11	12	13
Ingredients	Quantity (% w/v)
Axitinib	0.2	0.2	0.2
SBEβCD	8	8	8
Methane sulfonic acid	0.16	0.16	0.16
Hydroxypropyl methylcellulose	0.3	0.3	0.3
Benzalkonium chloride	0.01	0.01	0.01
Sodium N-lauroyl sarcosinate	0.06	0.06	0.06
Boric acid	0.45	0.45	0.45
Polyhexamethylene biguanide hydrochloride	0.02	0.02	0.02
Quil A	0.05	-	-
Salcaprozate sodium (SNAC)	-	0.05	-
Perifosine	-	-	0.05
Tromethamine	0.22	-	0.23
Water for Injection (WFI)	q.s.	q.s.	q.s.

S. No.	Tests	Results
S. No.	Tests	Ex. 11	Ex. 13
1	pH	7.0	7.1
2	Osmolality (mOsml/kg)	335	335
3	Viscosity	8.96 cP	8.02 cP

Example 14-15:

Preparation of ophthalmic solutions containing axitinib:

Ingredients	14	15
Ingredients	Quantity (% w/v)
Axitinib	0.2	0.2
SBEβCD	8	8
Methane sulfonic acid	0.16	0.16
Hydroxypropyl methylcellulose	0.3	0.3
Benzalkonium chloride	0.01	0.01
Sodium N-lauroyl sarcosinate	0.06	0.06
Boric acid	0.45	0.45
Polyhexamethylene biguanide hydrochloride	0.02	0.02
N-Dodecyl-Beta-D-Maltoside	0.05	-
Palmitoyl tripeptide 1	-	0.05
Tromethamine	0.23	0.23
Water for Injection (WFI)	q.s.	q.s.

S. No.	Tests	Results
S. No.	Tests	Ex. 14	Ex. 15
1	pH	7.0	6.9
2	Osmolality (mOsml/kg)	343	335

Example 16-17:

Preparation of ophthalmic solutions containing axitinib:

Ingredients	16	17
Ingredients	Quantity (% w/v)
Axitinib	0.2	0.3
SBEβCD	8.8	9.2
Methane sulfonic acid	0.16	0.23
Hydroxypropyl methylcellulose	0.3	0.3
Benzalkonium chloride	0.01	0.01
Tromethamine	0.21	0.3
Water for Injection (WFI)	q.s.	q.s.

S. No.	Tests	Results
S. No.	Tests	Ex. 16	Ex. 17
1	pH	6.9	6.9
2	Osmolality (mOsml/kg)	260	299
3	Viscosity	10.10 cP	7.88 cP
4	Drug Assay (Initial) at 2-8°C	107.1	-
5	Drug Assay (6 Months) at 2-8°C	107.0	-

Example 18-20:

	18	19	20
Ingredients	Quantity (% w/v)
Axitinib	0.3	0.1	0.1
SBEβCD	9.2	5	7
Methane sulfonic acid	0.23	0.08	0.08
Hydroxypropyl methylcellulose	0.3	0.3	0.3
Benzalkonium chloride	0.01	0.01	0.01
Polyhexamethylene biguanide hydrochloride HCl	-	0.02	0.02
Sodium N-lauroyl sarcosinate	0.06	-	-
Boric acid	0.05	0.9	0.5
Potassium sorbate	0.1		-
Tromethamine	0.25	0.20	0.20
Water for Injection (WFI)	q.s.	q.s.	q.s.

S. No.	Tests	Results
S. No.	Tests	Ex. 18	Ex. 19	Ex. 20
1	pH	6.0	6.9	7.0
2	Osmolality (mOsml/kg)	335	290	289
3	Viscosity	-	-	12.82 cP
4	Drug Assay (Initial)	-	99.9	99.6
5	Drug Assay (1 month) 2-8°C	-	100.8	99.0
6	Drug Assay (1 month) 25°C/40% RH	-	97.7	99.7
7	Drug Assay (1 month) 40°C/25%RH	-	99.1	100.5

Process:

Polymer phase: The required quantity of water for injection was taken in a vessel. Hydroxypropyl methylcellulose was added slowly into the vortex of vigorously agitated water for injection maintained at a suitable temperature of about 70-90°C using an overhead stirrer. Stirring was continued to obtain a homogeneous dispersion. The temperature was maintained throughout the preparation. Once homogeneous dispersion was formed, the temperature was decreased to room temperature and stirring was continued. The total volume was made up to the mark with water for injection and the phase was autoclaved to make it sterile.

Vehicle phase: Required quantity of water for injection was taken in a vessel or glass vial. Required excipients (boric acid, benzalkonium chloride, Polyhexamethylene biguanide hydrochloride, Sodium N-lauroyl sarcosinate, or tromethamine) were added. The solution was stirred after the addition of each excipient and was dissolved till a clear solution was formed.

Drug phase: Filtered water for injection was taken in a vessel or glass bottle and methane sulfonic acid was added to this and stirred. The drug was added followed by the addition of water for injection. This was heated to a suitable temperature of about 40-50 ℃ and was stirred. SBEβCD was added to the above solution and was kept under stirring at a suitable temperature of about 40-50℃, till it became a clear solution.

Bulk solution Preparation (Example 5-10, 14-21): Previously prepared clear vehicle phase solution was added to the sterile autoclaved polymer phase by passing through a suitable filter (0.2-micron sterile grade filter). The solution was stirred to ensure sufficient mixing. Drug phase solution was added to the above polymer-vehicle mixed phase by passing through a suitable filter (0.2-micron sterile grade filter). The solution was stirred to ensure sufficient mixing. The volume was made to the desired batch size. The bulk solution was filtered through a suitable filter (40 µ micron polishing filter).

Bulk solution Preparation (Example 11-13): Previously prepared clear vehicle phase solution was added to the sterile autoclaved polymer phase by passing through a suitable filter (0.2-micron sterile grade filter). Filtered water for injection was taken in a vessel or glass vial and the following excipient(s) was added based on their presence in the above formula i.e. Quil-A, SNAC, Perifosine, N-Dodecyl-Beta-D-Maltoside, or Palmitoyl tripeptide. The solution was stirred to ensure sufficient mixing. This solution was added by passing through a suitable filter (0.2-micron sterile grade filter) to previously prepared sterile autoclaved solution containing vehicle phase. Drug phase solution was added to the above polymer-vehicle mixed phase by passing through a suitable filter (0.2-micron sterile grade filter). The solution was stirred to ensure sufficient mixing. The volume was made to the desired batch size. The bulk solution was filtered through a suitable filter (40 µ micron polishing filter).

Filling: The filtered solution was aseptically filled in a suitable bottle with nitrogen purging, plugged, and capped with a tamper-proof closure.

Example 21:

Efficacy Assessment in a Swine Model of Laser-Induced Choroidal Neovascularization

Objective:

The objective was to evaluate the efficacy of compositions prepared in examples 16 and 17, in a model of laser-induced choroidal neovascularization (CNV) in domestic swine.

Experimental Design:

Swine were enrolled in 4 groups. Animals underwent laser-induced CNV procedures in both eyes (OU) on Day 1, followed by treatment. Animals in all groups (n = 6/group) received a 50 µL topical dose OU twice daily (BID). Group 1 received 0.9% saline; Group 2 received composition given in example 16; Group 3 received composition given in example 17; Group 4 received 50 µL intravitreal (IVT) injection of 40 mg/mL Aflibercept (positive control) OU on Day 1. Animals underwent ocular examinations (OEs), fluorescein angiography (FA), and fundus imaging.

Laser-Induced Choroidal Neovascularization:

The animals were fasted the night prior to injections. On Day 1, animals received buprenorphine (0.01-0.05 mg/kg) intramuscularly (IM) for pain management, and atropine (0.05 mg/kg IM) to dry oral secretions. At least 15 minutes prior to anesthesia administration, 1% tropicamide HCl was applied topically to dilate the eyes. Animals were sedated with a ketamine/dexmedetomidine cocktail (10/0.075 mg/kg IM). A wire eyelid speculum was placed, and the cornea was kept moistened using topical eyewash. An 810 nm diode laser delivered through an indirect ophthalmoscope was used to create ~6 single laser spots between retinal veins. The procedure was repeated on the contralateral eye. Following laser-induced CNV, animals received atipamezole (0.5 mg/kg IM) to reverse the effects of the anesthetic and were returned to their cages, placed in sternal or lateral recumbency, and monitored every 15-30 minutes until recovered. There were no abnormal observations during laser-induced CNV procedures noted in the study records.

Dosing:

With the animal manually restrained, the upper eyelid was gently elevated to expose the cornea, and compositions were applied to the cornea via a calibrated air displacement pipette without contacting the cornea with the pipette tip. The procedure was repeated on the contralateral eye. The animal was allowed to blink several times while restrained to distribute the solution over the eye. Animals were dosed 1 hour prior to FA or fundus imaging where applicable.

Results:

Ocular Examinations (OE)

OEs were performed using a slit lamp biomicroscope and indirect ophthalmoscope to evaluate toxicologic or inflammatory changes of the ocular adnexa, cornea, and anterior and posterior segments of the eye. The semiquantitative preclinical ocular toxicology scoring (SPOTS) system was used for scoring. A topical mydriatic (1% tropicamide HCl) was administered prior to OEs to facilitate examination of the posterior segment. All OEs were found satisfactory.

Color Fundus Imaging

Animals were given atropine (0.05 mg/kg) IM and anesthetized with a ketamine/dexmedetomidine (10/0.075 mg/kg IM). One drop each of 1% tropicamide HCl, 0.5% proparacaine HCl, and a topical ophthalmic lubricant were applied OU, and a wire eyelid speculum was placed as needed. Approximately 2-4 hours post-morning topical dose, animals underwent color fundus imaging procedures of the posterior section of the eye with the optic nerve head (ONH) oriented centrally. Superior and inferior images were taken with the RetCam3 (Natus) to visualize changes in the fundus over time. Fundus images were found satisfactory.

Fluorescein Angiography (FA):

Animals were fasted on the morning of Day 8. Animals were given atropine (0.05 mg/kg) IM and anesthetized with a ketamine/dexmedetomidine (10/0.075 mg/kg IM). One drop each of 1% tropicamide HCl, 0.5% proparacaine HCl, and a topical ophthalmic lubricant was applied OU, and a wire eyelid speculum was placed as needed. Full FA was performed 1-3 minutes after intravenous (IV) sodium fluorescein injection (12 mg/kg). For all FA images, the camera light intensity was fixed to the same level. Following imaging animals received atipamezole (0.5-0.8 mg/kg IM) to reverse the effects of the dexmedetomidine and were allowed to recover normally from the procedure.

The corrected total lesion fluorescence (CTLF) was measured for each lesion. An 8-bit cropped image was created for each lesion from the FA dataset using FIJI/Image. A region of interest (ROI) was drawn around the lesion (i.e., the pooled fluorescein) as well as an ROI adjacent to the lesion to provide a background pixel intensity value. Mean pixel intensity and area was measured for each ROI, and thresholding was used to remove the hyperfluorescent vasculature from the pixel intensity measurement values. The CTLF was calculated using the following equation: CTLF = (Mean Intensity^Lesion x Area^Lesion) - (Mean Intensity^Background x Area^Lesion).

Statistical Method:

One way ANOVA followed by Dunnett multiple comparisons was used.

Results and Conclusion:

Eyes treated with 0.9% saline had a significantly larger CTLF value than eyes receiving treatments as per the present invention. These below represented results show that the compositions prepared as per the present invention were effective. represents the change in CTLF over time.

Groups	Corrected Total Lesion Fluorescence (CTLF) Mean ± SD
Groups	Day 8
0.9% saline	1384719 ± 550654
Ex. 16	472925 ± 69004.1
Ex. 17	535989 ± 157877
Aflibercept	293644.5 ± 63417.38

Example 22: Pharmacokinetic Study

Objective:

The objective of this study was to quantify axitinib in the pig retina, vitreous humor, choroid, sclera, iris-ciliary body, and aqueous humor following repeated ocular administration.

Procedure:

Animals of Groups 2 and 3 from example 21 were continued with the treatment till day 15. On day 15, after the first dose of ocular treatment (Ex. 16 and Ex. 17) animals were euthanized with an overdose of sodium pentobarbital (150 mg/kg IV or intracardiac), followed by auscultation to ensure death.

Ocular Tissue Collections:

Ocular tissues (retina, vitreous humor, RPE/choroid, sclera, iris and ciliary body, and aqueous humor) were collected from both the eyes of animals of Groups 2 and 3 and weighed. To prevent the transfer of test drug between the tissue of the eyes, instruments were thoroughly rinsed with phosphate-buffered saline (PBS), followed by ethanol, followed by PBS, and blotted dry. All tissues were placed into individual pre-labeled vials, reweighed, frozen on dry ice, and stored at -80°C.

Bioanalytical method :

LC-MS/MS analytical method was used for axitinib assay in pig aqueous humor, iris and ciliary body, vitreous humor, RPE/choroid, retina, and sclera.

Sample Preparation:

A fixed amount of water was added for the homogenization of each matrix. The concentration was then calculated based on the sample weights.

Statistical Analysis:

Pairwise multiple comparison was performed with Tukey’s adjustment.

Results:

The results as represented in the below table show the concentrations of axitinib in the posterior tissues of the eyes.

Concentration (ng/g) ± SD
S. No.	Eye Tissues	Example 16	Example 17
1	Retina	3.7129 ± 1.2326	3.6348 ± 1.2442
2	Vitreous humor	0.02491 ± .028325	0.02118 ± 0.013615
3	Sclera	55.299 ± 29.323	62.089 ± 47.853
4	RPE-Choroid	196.76 ± 75.484	202.22 ± 53.691
5	Aqueous humor	2.9750 ± 1.81935	2.9887 ± 2.17916
6	Iris-ciliary body	262.86 ± 181.81	172.49 ± 33.931

Claims

A topical pharmaceutical composition comprising:
axitinib, its isomer, or a salt thereof;

one or more solubility enhancer; and

one or more precipitation inhibitor.
The composition according to claim 1, wherein the composition is an ophthalmic solution.
The composition according to any one of the preceding claims, wherein solubility enhancer is an acid selected from the group consisting of organic acid, mineral acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein precipitation inhibitor is selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:50.
An ophthalmic solution composition comprising:
axitinib, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;

one or more solubility enhancer in an amount of about 0.001% to about 30% w/v;

one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v; and

one or more pharmaceutically acceptable excipient.
The composition according to any one of the preceding claims, wherein the composition further comprises water as a vehicle.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:4.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:50.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:40.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:30.
The composition according to any one of the preceding claims, wherein solubility enhancer is an acid selected from the group consisting of organic acid, mineral acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein the organic acid is selected from the group consisting of alkyl sulfonic acid, acetic acid, citric acid, malic acid, formic acid, lactic acid, oxalic acid, tartaric acid, uric acid, maleic acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein the organic acid is alkyl sulfonic acid.
The composition according to any one of the preceding claims, wherein alkyl sulfonic acid is selected from the group consisting of methane sulfonic acid, butane sulfonic acid, propane sulfonic acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein the alkyl sulfonic acid is methane sulfonic acid.
The composition according to any one of the preceding claims, wherein mineral acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein precipitation inhibitor is selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof.
The composition according to any one of the preceding claims, wherein cyclic polymer is selected from the group consisting of cyclic oligosaccharide, cyclic polysaccharide, cyclic non-oligosaccharides, or a combination thereof.
The composition according to any one of the preceding claims, wherein cyclic oligosaccharide is cyclosophoran, cycloamylose, cyclotetraglucose, cyclodextrin derivative selected from the group consisting of 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD), 2-hydroxypropyl-γ-cyclodextrin, methyl-β-cyclodextrin, carboxymethyl β-cyclodextrin, or a combination thereof.
The composition according to any one of the preceding claims, wherein cyclic polysaccharide is cyclic β-1,2-glucan.
The composition according to any one of the preceding claims, wherein cyclic non-oligosaccharide is selected from the group consisting of cyclo poly(styrene), cyclo-poly(lactide), cyclo poly(ε-caprolactone) (PCL), cyclo poly(ethylene oxide), or a combination thereof.
The composition according to any one of the preceding claims, wherein the linear polymer is selected from the group consisting of linear oligosaccharide, linear polysaccharide, linear cellulosic polymer, and their derivatives, or a combination thereof.
The composition according to any one of the preceding claims, wherein the linear oligosaccharide is selected from the group consisting of maltodextrin, raffinose, stachyose, fructo-oligosaccharide, or a combination thereof.
The composition according to any one of the preceding claims, wherein the linear polysaccharide is selected from the group consisting of starch and its derivatives, amylose, amylopectin, modified starch, carboxymethyl starch, glycogen, cellulose, hemicellulose, pectin, hydrocolloid, or a combination thereof.
The composition according to any one of the preceding claims, wherein the linear polymer is a carbomer, polycarbophil, polyvinyl alcohol, polyvinyl pyrrolidine, polyethylene glycol (PEG), hyaluronic acid (HA), cellulose derivative selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, hydroxy ethyl cellulose, or a combination thereof.
The composition according to any one of the preceding claims, wherein the precipitation inhibitor is sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose, and the solubilizing agent is methane sulfonic acid.
The composition according to any one of the preceding claims, wherein the composition further comprises a penetration enhancer.
The composition according to any one of the preceding claims, wherein the penetration enhancer is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of benzalkonium chloride, protamine sulfate, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), Palmitoyl tripeptide, Quil A, DMSO, EDTA and sodium glycocholate, or a combination thereof.
The composition according to any one of the preceding claims, further comprises a preservative, pH adjusting agent, or a combination thereof.
The composition according to any one of the preceding claims, wherein preservative is present in an amount of about 0.001% to about 4% w/v and selected from the group consisting of benzalkonium chloride, biguanide compound, acylated amino acid, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, potassium sorbate, sodium borate, chlorhexidine digluconate, polyquad, perborate-based preservatives, mercuric compounds, and zinc polyol complexes, or a combination thereof.
The composition according to any one of the preceding claims, wherein the preservative is a biguanide compound selected from the group consisting of polyhexamethylene biguanide, alkyl-biguanide, polyoxyalkylene diamine biguanide or their water-soluble salt; 1,1'-hexamethylene-bis-{5-(4-chlorophenyl)-biguanide}; 1,1'-hexamethylene-bis-{5-(2-ethylhexyl) biguanide}, 1,1 '-hexamethylene-bis-{5-(4-fluoro phenyl)-biguanide}; (N,N"-bis(2-ethyl hexyl)-3, 12-diimino-2,4, 11, 13-tetraazatetra decanediimidamine, chlorhexidine or their salts, or a combination thereof.
The composition according to any one of the preceding claims, wherein the preservative is acylated amino acid selected from a group consisting of acyl sarcosines or sarcosinates, acyl glutamates, acyl glycinates, acyl aspartates, acyl taurates, acyl malonates or acyl amino-malonates, their salts, or a combination thereof.
The composition according to any one of the preceding claims, wherein the composition comprises benzalkonium chloride, N-lauroyl sarcosine sodium, polyhexamethylene biguanide hydrochloride, or a combination thereof.
The composition according to any one of the preceding claims, wherein pH-adjusting agent is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof.
An ophthalmic solution composition comprising:
axitinib, its isomer, or a salt thereof in an amount of about 0.01% to about 5% w/v;

about 0.05% to about 10% w/v of methane sulfonic acid;

about 1% to about 20% w/v of sulfobutyl ether β-cyclodextrin;

about 0.05% to about 10% w/v hydroxypropyl methyl cellulose;

one or more pharmaceutically acceptable excipient; and

water.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:0.5 to about 1:10.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the methane sulfonic acid ranges from about 1:2 to about 1:4.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:0.5 to about 1:50.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:0.5 to about 1:40.
The composition according to any one of the preceding claims, wherein the molar ratio between the axitinib, its isomer, or a salt thereof, and the sulfobutyl ether β-cyclodextrin ranges from about 1:1 to about 1:30.
The composition according to any one of the preceding claims for use in treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity.
The composition according to any one of the preceding claims, delivers axitinib in the posterior segment of the eye at a concentration of up to 5000 times higher than the IC₅₀ value of axitinib.
The composition according to any one of the preceding claims, delivers axitinib in the posterior segment of the eye at a concentration of about 100 to about 300 ng/gm.
The composition according to any one of the preceding claims, wherein the composition does not comprise any non-aqueous vehicle.
A topical pharmaceutical composition comprising:
a tyrosine kinase inhibitor, its isomer, or a salt thereof in an amount of about 0.01% to about 10% w/v;

one or more solubility enhancer in an amount of about 0.001% to about 30% w/v;

one or more precipitation inhibitor in an amount of about 0.05% to about 30% w/v; and

one or more pharmaceutically acceptable excipient.
The composition according to any one of the preceding claims, wherein the tyrosine kinase inhibitor is selected from the group consisting of axitinib, ponatinib, sunitinib, lenvatinib, pazopanib, nintedanib, cabozantinib, vandetanib, sorafenib and regorafenib, their isomers or salts thereof.
The composition according to any one of the preceding claims, wherein the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10.
The composition according to any one of the preceding claims, wherein the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:2 to about 1:4.
The composition according to any one of the preceding claims, wherein the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1: to about 1:50.
The composition according to any one of the preceding claims, wherein the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:0.5 to about 1:40.
The composition according to any one of the preceding claims, wherein the molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the precipitation inhibitor ranges from about 1:1 to about 1:30.
The composition according to any one of the preceding claims, wherein the composition further comprises water as a vehicle.
The composition according to any one of the preceding claims, wherein solubility enhancer is an acid selected from the group consisting of organic acid, mineral acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein the organic acid is selected from the group consisting of alkyl sulfonic acid, acetic acid, citric acid, malic acid, formic acid, lactic acid, oxalic acid, tartaric acid, uric acid, maleic acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein the organic acid is alkyl sulfonic acid.
The composition according to any one of the preceding claims, wherein alkyl sulfonic acid is selected from the group consisting of methane sulfonic acid, butane sulfonic acid, propane sulfonic acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein the alkyl sulfonic acid is methane sulfonic acid.
The composition according to any one of the preceding claims, wherein mineral acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, or a combination thereof.
The composition according to any one of the preceding claims, wherein precipitation inhibitor is selected from the group consisting of cyclic polymer, linear polymer, or a combination thereof.
The composition according to any one of the preceding claims, wherein cyclic polymer is selected from the group consisting of cyclic oligosaccharide, cyclic polysaccharide, cyclic non-oligosaccharides, or a combination thereof.
The composition according to any one of the preceding claims, wherein cyclic oligosaccharide is cyclosophoran, cycloamylose, cyclotetraglucose, cyclodextrin derivative selected from the group consisting of 2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD), 2-hydroxypropyl-γ-cyclodextrin, methyl-β-cyclodextrin, carboxymethyl β-cyclodextrin, or a combination thereof.
The composition according to any one of the preceding claims, wherein cyclic polysaccharide is cyclic β-1,2-glucan.
The composition according to any one of the preceding claims, wherein cyclic non-oligosaccharide is selected from the group consisting of cyclo poly(styrene), cyclo-poly(lactide), cyclo poly(ε-caprolactone) (PCL), cyclo poly(ethylene oxide), or a combination thereof.
The composition according to any one of the preceding claims, wherein the linear polymer is selected from the group consisting of linear oligosaccharide, linear polysaccharide, linear cellulosic polymer, and their derivatives, or a combination thereof.
The composition according to any one of the preceding claims, wherein the linear oligosaccharide is selected from the group consisting of maltodextrin, raffinose, stachyose, fructo-oligosaccharide, or a combination thereof.
The composition according to any one of the preceding claims, wherein the linear polysaccharide is selected from the group consisting of starch and its derivatives, amylose, amylopectin, modified starch, carboxymethyl starch, glycogen, cellulose, hemicellulose, pectin, hydrocolloid, or a combination thereof.
The composition according to any one of the preceding claims, wherein the linear polymer is a carbomer, polycarbophil, polyvinyl alcohol, polyvinyl pyrrolidine, polyethylene glycol (PEG), hyaluronic acid (HA), cellulose derivative selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, hydroxy ethyl cellulose, or a combination thereof.
The composition according to any one of the preceding claims, wherein the precipitation inhibitor is sulfobutyl ether β-cyclodextrin and hydroxypropyl methyl cellulose, and the solubilizing agent is methane sulfonic acid.
The composition according to any one of the preceding claims, wherein the composition further comprises a penetration enhancer.
The composition according to any one of the preceding claims, wherein the penetration enhancer is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of benzalkonium chloride, protamine sulfate, synthetic N-acylated amino acid (SNAC) / salcaprozate sodium, perifosine, N-Dodecyl-Beta-D-Maltoside (DDM), Palmitoyl tripeptide, Quil A, DMSO, EDTA and sodium glycocholate, or a combination thereof.
The composition according to any one of the preceding claims, further comprises preservative, pH adjusting agent, or a combination thereof.
The composition according to any one of the preceding claims, wherein preservative is present in an amount of about 0.001% to about 4% w/v and selected from the group consisting of benzalkonium chloride, biguanide compound, acylated amino acid, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxyethanol, phenylethyl alcohol, sorbic acid, methyl and propyl parabens, potassium sorbate, sodium borate, chlorhexidine digluconate, polyquad, perborate-based preservatives, mercuric compounds, and zinc polyol complexes, or a combination thereof.
The composition according to any one of the preceding claims, wherein the preservative is a biguanide compound selected from the group consisting of polyhexamethylene biguanide, alkyl-biguanide, polyoxyalkylene diamine biguanide or their water-soluble salt; 1,1'-hexamethylene-bis-{5-(4-chlorophenyl)-biguanide}; 1,1'-hexamethylene-bis-{5-(2-ethylhexyl) biguanide}, 1,1 '-hexamethylene-bis-{5-(4-fluoro phenyl)-biguanide}; (N,N"-bis(2-ethyl hexyl)-3, 12-diimino-2,4, 11, 13-tetraazatetra decanediimidamine, chlorhexidine or their salts, or a combination thereof.
The composition according to any one of the preceding claims, wherein the preservative is acylated amino acid selected from a group consisting of acyl sarcosines or sarcosinates, acyl glutamates, acyl glycinates, acyl aspartates, acyl taurates, acyl malonates or acyl amino-malonates, their salts, or a combination thereof.
The composition according to any one of the preceding claims, wherein the composition comprises benzalkonium chloride, N-lauroyl sarcosine sodium, polyhexamethylene biguanide hydrochloride, or a combination thereof.
The composition according to any one of the preceding claims, wherein pH-adjusting agent is present in an amount of about 0.01% to about 5% w/v and selected from the group consisting of boric acid, citric acid, hydrochloric acid, acetate buffers, disodium phosphate, monosodium phosphate, sodium borate, sodium citrate, sodium hydroxide, tromethamine, and potassium phosphate, or a combination thereof.
The composition according to any one of the preceding claims, has a pH in the range of about 5.0 to 8.0.
The composition according to any one of the preceding claims, has a pH in the range of about 6.0 to 8.0.
The composition according to any one of the preceding claims, has an osmolality in the range of about 150 to 450 mOsml/kg.
The composition according to any one of the preceding claims, has an osmolality in the range of about 250 to 375 mOsml/kg.
The composition according to any one of the preceding claims, wherein the composition has one or more following characteristics:
molar ratio between the tyrosine kinase inhibitor, its isomer, or a salt thereof, and the solubility enhancer ranges from about 1:0.5 to about 1:10;

a pH in the range of about 6.0 to 8.0; or

an osmolality in the range of about 250 to 375 mOsml/kg.
The composition according to any one of the preceding claims for use in treatment or prevention of age-related macular degeneration (AMD), macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, Myopic Choroidal Neovascularization (mCNV), or retinopathy of prematurity.
The composition according to any one of the preceding claims, delivers tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of up to 5000 times higher than the IC₅₀ value of the tyrosine kinase inhibitor.
The composition according to any one of the preceding claims, delivers tyrosine kinase inhibitor in the posterior segment of the eye at a concentration of about 100 to about 300 ng/gm.
The composition according to any one of the preceding claims, wherein the composition does not comprise any non-aqueous vehicle.